Nitrogen-containing heterocyclic compound, pharmaceutical composition thereof and application thereof

Abstract

Disclosed is a nitrogen-containing heterocyclic compound, pharmaceutical composition thereof and application thereof. The present disclosure provides a nitrogen-containing heterocyclic compound of formula I, a pharmaceutically acceptable salt thereof, a prodrug thereof, a stereoisomer thereof, a tautomer thereof or an isotopically labeled compound thereof. The nitrogen-containing heterocyclic compounds as represented in Formula I in the present disclosure have good inhibitory effects on cells of various mutations such as KRAS G12C, KRAS G12D, KRAS G12V, KRAS Q61H and other mutations, as well as on KRAS-amplified wild-type cells, and are expected to treat and / or prevent a wide range of diseases associated with Ras.

Description

[0001] Nitrogen-Containing Heterocyclic Compound, Pharmaceutical composition Thereof and Application Thereof Technical field The present disclosure relates to a nitrogen-containing heterocyclic compound, pharmaceutical composition thereof and application thereof. Background Ras (Rat sarcoma viral oncogene) was first found in rat sarcoma. There are three members in the ras gene family of mammals, namely H-ras (HRAS), K-ras (KRAS) and N-ras (NRAS), where the fourth exon of K-ras has variants A and B. Ras gene is widely found in various eukaryotes such as mammals, fruit flies, fungi, nematodes and yeasts, and is expressed at various levels in different tissues, where H-Ras is mainly expressed in skin and skeletal muscle, K-Ras is mainly expressed in colon and thymus, and N-Ras is expressed at a high level in testis. Ras protein regulates and controls signal transduction by switching the binding to GTP / GDP as a molecular switch in cell signal transduction, thereby regulating the life processes such as proliferation, differentiation, senescence and apoptosis of cells. The mutated forms of RAS are closely associated with the occurrence and development of human tumors, and are present in about 30% of human tumors. KRAS mutation is most common and accounts for approximately 85% of cases, and NRAS and HRAS account for 12% and 3%, respectively. KRAS mutation is mainly found in pancreatic, colorectal and lung cancers, NRAS mutation is common in melanoma and acute myelogenous leukemia, and HRAS mutation is common in bladder and head and neck cancers. Ras proto-oncogene mutation occurs mainly by point mutation. More than 150 different Ras point mutations have been found, with mutations in the glycine at positions 12 and 13 and glutamine at position 61 being the most common. For decades, efforts have been made to develop small molecule inhibitors targeting Ras. Scientists have been hoping to develop competitive inhibitors of GTP that act directly on the Ras protein. However, this has not been successful because of the strong affinity between GTP and Ras (pmol / L level), the high concentration of GTP in cells (0.5 mM), the lack of a pocket in the RAS protein structure that facilitates the binding of small molecules, and the like. In recent years, some advances have been made in drug development using the allosteric site of KRasG12Cmutant. In 2013, a team of researchers reported the discovery about K-Ras G12C small molecule inhibitors (Nature, 2013, 503, 548-551). They identified a novel binding pocket located below the molecular switch II region from K-Ras G12C mutant. Those inhibitors bind to the allosteric pocket and covalently bind to nearby Cys12, thereby selectively inhibiting the activation of K-Ras G12C. Other researchers have reported KRAS inhibitors with cellular activity (Science, 2016, 351, 604-608). As one of the most important cancer driver genes, the mutation of KRAS G12C provides the possibility of irreversible covalent small molecule drug design, and the research and development of the corresponding drugs have become the hotspot of the global anti-tumor drug research and development after the breakthrough of related scientific research work. In May 2021, Amgen's KRAS G12C inhibitor Lumakras received accelerated approval from the U.S. FDA, achieving a major breakthrough in the “non-druggable” nature of KRAS. Despite the major breakthrough in KRAS G12C inhibitor research, current clinical studies of KRAS G12C inhibitors have shown that they are not effective for long periods of time and are prone to drug resistance. Meanwhile, numerous other mutations, including cancers harboring KRAS G12D, G12V, G13D, G12R, G12S, G12A and other mutations, as well as KRAS wild-type amplification, lack effective drugs. Therefore, there is an urgent need to find drugs that target KRAS mutations. In conclusion, after decades of unremitting efforts, the understanding of Ras has been gradually improved, but only one drug for KRAS G12C mutation has been marketed so far, and there is no particularly effective treatment for other different mutations. The search for compounds with good inhibitory effects on Ras remains a hot and difficult research area in new drug development. Content of the present invention The technical problem to be solved by the present disclosure is the lack of effective drugs serving as Ras inhibitors for clinical treatment in the prior art. Therefore, the present disclosure provides a nitrogen-containing heterocyclic compound, pharmaceutical composition thereof and application thereof, and the nitrogen-containing heterocyclic compound is expected to treat or prevent various RAS-related diseases. The present disclosure solves the above problem by the following technical schemes. The present disclosure provides a nitrogen-containing heterocyclic compound of formula I, a pharmaceutically acceptable salt thereof, a prodrug thereof, a stereoisomer thereof, a tautomer thereof or an isotopically labeled compound thereof: wherein “ “ represents a single or double bond; is phenyl, “5- to 7-membered heterocycloalkenyl containing 1–3 heteroatoms independently selected from O, S and N”, “5- to 7-membered heteroaryl containing 1–3 heteroatoms independently selected from O, S and N” or 5- to 7-membered cycloalkenyl; wherein D1is C, CH or N; D2is , wherein Z1and Z2are independently a bond, CH, CH2, O, S, N or NH; r is 0, 1, 2, 3 or 4; R5is independently deuterium, halogen, C1-6alkyl, C1-6alkyl substituted with one or more halogen, C3-10cycloalkyl, hydroxyl, C1-6alkyl-O-, C1-6alkyl-S-, amino, C1-6alkyl-NH-, C2-6alkenyl, nitro or C3-10cycloalkyl-O-; X1and X2are independently CRbor N, and X1and X2are not both CRb; Y1is O, S, NH, CH2or Y2is NR2, O or S; m1, m2 and n are independently 0, 1, 2, 3 or 4; Rbis hydrogen, halogen or cyano; R1is C6-20aryl, “5- to 12-membered heteroaryl containing 1–4 heteroatoms independently selected from O, S and N”, C6-20aryl substituted with one or more R1-1or “5- to 12-membered heteroaryl containing 1–4 heteroatoms independently selected from O, S and N” substituted with one or more R1-2; provided that when multiple substituents are present, the substituents are the same or different; R1-1and R1-2are independently deuterium, halogen, -ORc, cyano, azide, -C(=O)R11, -NR12R13, - C(=O)OR14, -C(=O)NR15R16, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -B(ORx) (ORy), “4- to 7-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O, S and N”, C6-20aryl, “5- to 7-membered heteroaryl containing 1 or 2 heteroatoms independently selected from O, S, and N”, C1-6alkyl substituted by one or more R1-1-1, C1-6alkyl-O- substituted by one or more R1-1-2, C3-10cycloalkyl substituted by one or more R1-1-3, “4- to 7-membered heterocyclic cycloalkyl containing 1 or 2 heteroatoms independently selected from O, S, and N” substituted by one or more R1-1-4, C6-20aryl substituted with one or more R1-1-5, or “5- to 7-membered heteroaryl containing one or two heteroatoms independently selected from O, S, and N” substituted with one or more R1-1-6; provided that when multiple substituents are present, the substituents are the same or different; or, when the number of R1-1or R1-2is more than one, two optional R1-1or R1-2are connected, together with the atoms on the ring to which they are attached, independently form 3- to 8-membered cyclic olefin; R2, Rc, R12and R13are independently hydrogen, C1-6alkyl, -C(=O)Rc1, -C(=O)ORc2, - C(=O)NRc3Rc4, -SO2Rc5, or C1-6alkyl substituted with one or more Rc10; Rc1, Rc2, Rc3, Rc4, Rc5, Rc6, Rc7, Rc8and Rc9are independently hydrogen, C1-20alkyl, C3-10cycloalkyl, “4- to 7-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O, S and N”, C6-20aryl, “5- to 7-membered heteroaryl containing 1 or 2 heteroatoms independently selected from O, S and N”, C1-20alkyl substituted with one or more R4-1-1, C3-10cycloalkyl substituted with one or more R4-1-2, “4- to 7-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O, S and N” substituted with one or more R4-1-3, C6-20aryl substituted with one or more R4-1-4, “5- to 7-membered heteroaryl containing 1 or 2 heteroatoms independently selected from O, S and N”, “5- to 7-membered heteroaryl containing 1 or 2 heteroatoms independently selected from O, S and N” substituted with one or more R4-1-5, - NRc51Rc52, -(C1-6alkylene-O)p- C1-6alkyl, p is 1, 2,3 or 4; R1-1-1, R1-1-2, R1-1-3, R1-1-4, R1-1-5, R1-1-6, R4-1-1, R4-1-2, R4-1-3, R4-1-4and R4-1-5are independently cyano, halogen, hydroxyl, nitro, C1-6alkyl-O-, C1-6alkyl, C1-6alkyl substituted with one or more R31, C3-10cycloalkyl, “4- to 7-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O, S, and N”, C6-20aryl, “5- to 7-membered heteroaryl containing 1 or 2 heteroatoms independently selected from O, S, and N”, - B(ORx) (ORy), -C(=O)R21, -NR22R23, -C(=O)OR24, - OC(=O)R32, -C(=O)NR25R26, -COOH, -C(=O)OR27or -OC(=O)OR28; Rc10is -OC1-6alkyl, hydroxyl, substituted with C1-6alkyl, C6-20aryl substituted with one or more -B(ORx)(ORy), “5- to 7-membered heteroaryl containing 1 or 2 heteroatoms independently O selected from O, S, and N” substituted with one or more Rc10-1,or -OC(=O)R29; Rc10-1 is independently C1-6alkyl or nitro; or, optional R2and Rb, optional R2and R5together with the atoms to which they are attached, independently form “5- to 12-membered heterocyclic alkenyl containing 2 to 4 heteroatoms, two of which are N, and the other heteroatoms independently selected from O, S, and N”, or “5- to 12- membered heterocyclic alkenyl containing 2 to 4 heteroatoms, two of which are N, and the other heteroatoms independently selected from O, S, and N,” substituted with one or more Ra; Rxand Ryare independently hydrogen, C1-6alkyl, or Rxand Ryeach with the attached oxygen atom form five-membered ring substituted with one or more C1-6alkyl; R4is independently deuterium, halogen, cyano, hydroxyl, C1-6alkyl, C1-6alkyl substituted with one or more R4-1, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C1-6alkyl-O-, -O-C1-6alkyl substituted with one or more R4-2, -S-C1-6alkyl, -S-C1-6alkyl substituted with one or more R4-3, O=, O-C3-10cycloalkyl, -C(=O)R4a, -NR4b1R4b2, -C(=O)OR4cor -C(=O)NR4d1R4d2; or, when n is 2, 3 or 4, two optional R4are connected, together with the atoms to which they are attached form 3- to 8- membered carbocyclic ring, 3- to 8-membered carbocyclic ring substituted with one or more R4-4, “ 4- to 8-membered heterocyclic ring containing 1 to 3 heteroatoms independently selected from O, S, and N”, or, “ 4- to 8-membered heterocyclic ring containing 1 to 3 heteroatoms independently selected from O, S, and N” substituted with one or more R4-5; R4-1, R4-2, R4-3, R4-4, R4-5and Raare independently halogen, C1-6alkyl, C2-6alkenyl, cyano, hydroxyl, C1-6alkyl-O-, -NR4iR4j, -C(=O)OR4eor -C(=O)NR4f1R4f2; or, R4-5is O=; R4a, R4b1, R4b2, R4c, R4d1, R4d2, R4e, R4f1, R4f2, R4iand R4jare independently hydrogen, C1-6alkyl or C2-6alkenyl; L1is a bond, C1-6alkylene, -C(=O)-, -O(RL-1)n1-, -S(RL-2)n2- or -NRL-3(RL-4)n3-; RL-1, RL-2and RL-4are independently C1-6alkylene or C1-6alkylene substituted with one or more deuterium ; RL-3is hydrogen or C1-6alkyl; n1, n2 and n3 are independently 0 or 1; R3is C3-12cycloalkyl, C3-12cycloalkyl substituted with one or more R3-1, “4- to 12-membered heterocycloalkyl containing 1–3 heteroatoms independently selected from O, S and N”, “4- to 12- membered heterocycloalkyl containing 1–3 heteroatoms independently selected from O, S and N” substituted with one or more R3-2, C1-6alkyl, C1-6alkyl substituted with one or more R3-3, C2-6alkenyl substituted with one or more R3-4, -ORd, -SRd1, -NRe1Re2or -C(=O)NRe3Re4; provided that when multiple substituents are present, the substituents are the same or different; R3-1, R3-2, R3-3and R3-4are independently C1-6alkyl, C1-6alkyl substituted with one or more R3-1-1, C6-20aryl substituted with one or more R3-1-5, hydroxyl, azide, Ar, C1-6alkyl-O-, -CH2-O-Ar, halogen, O=, -NRe5Re6, -C(=O)NRe7Re8or ; Ar is “5-12-membered heteroaryl containing 1-3heteroatoms independently selected from O, N and S” substituted with one or more R3-1-4; or, R3-1and R3-2are independently -L2-M; L2is -L21-L22-L23-L24-L25-L26; L21, L23and L25are independently a bond, O, S, NH, C(O)NH or C1-6alkylene; L22and L24are independently a bond, C3-10cycloalkyl, “4- to 7-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O, S and N”, C6-20aryl, or , “5- to 7-membered heteroaryl containing 1 or 2 heteroatoms independently selected from O, S, and N”; L26is a bond, O, S, NH or C(O)NH; R4g, R4h, Re17and Re18are independently hydrogen, halogen, C1-6alkyl, C1-6alkyl substituted with one or more halogen, cyano, -C(=O)Re171, -C(=O)ORe172or -C(=O)NRe173Re174; or, R4gand R4h, Re17and Re18, together with the atom to which they are attached form 3- to 8-membered carbocyclic ring, or “4- to 8-membered heterocyclic ring containing 1 to 3 heteroatoms independently selected from O, S, and N”; Rd, Rd1, Re1, Re2, Re3and Re4are independently hydrogen, C1-6alkyl, C3-10cycloalkyl, “4- to 10- membered heterocycloalkyl containing 1–3 heteroatoms independently selected from O, S and N”, or, C1-6alkyl substituted with one or more R3-1-2; R3-1-1, R3-1-2, R3-1-5and R3-1-4are independently deuterium, cyano, halogen, hydroxyl, C1-6alkyl, C2-6alkenyl, C1-6alkyl-O-, C1-6alkyl-O- substituted with one or more halogen, C1-6alkyl substituted with one or more halogen, -C(=O)Re9, -NRe10Re11, -C(=O)ORe12, -C(=O)NRe13Re14, - OC(=O)NRe15Re16, “4- to 10-membered heterocycloalkyl containing 1–3 heteroatoms independently selected from O, S and N”, or, “4- to 10-membered heterocycloalkyl containing 1–3 heteroatoms independently selected from O, S and N” substituted with one or more R3-1-1-1; or, two optional R3-1-5are connected, together with the atoms to which they are attached form “4- to 10- membered heterocycloalkyl containing 1–3 heteroatoms independently selected from O, S and N” substituted with one or more R3-1-1-2; R3-1-1-1and R3-1-1-2are independently, halogen,C1-6 alkyl or C6-20 aryl substituted with one or more R3-1-1-1-1; R3-1-1-1-1is halogen or C1-6alkyl substituted with one or more halogen; Re5, Re6, Re7, Re8, Re9, Re10, Re11, Re12, Re13, Re14, Re15, Re16, Re171, Re172, Re173and Re174are independently hydrogen or C1-6alkyl; or, R12and R13, R15and R16, Rc3and Rc4, R22and R23, R25and R26, R4b1and R4b2, R4d1and R4d2, R4f1and R4f2, R4iand R4j, Re1and Re2, Re3and Re4, Re5and Re6, Re7and Re8, Re10and Re11, Re13and Re14, Re15and Re16, Re173and Re174together with the atom N to which they are attached form “4- to 12- membered heterocycloalkyl containing 1–3 heteroatoms, of which one is N, the other independently selected from O, S and N”, or , “4- to 12-membered heterocycloalkyl containing 1–3 heteroatoms, of which one is N, the other independently selected from O, S and N” substituted with one or more R3-1-3; R3-1-3is independently deuterium, cyano, halogen, hydroxyl, C1-6alkyl-O-, C1-6alkyl, C1-6alkyl substituted with one or more R33, “4- to 7-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O, S and N” or -C(=O)OR30; Rc51, Rc52, R11, R21, R14, R15, R16, R24, R25, R26, R27, R28and R30are independently hydrogen or C1-6alkyl; R29is hydrogen, C1-6alkyl or -NRmRn; R31is hydrogen, C1-6alkyl, -OC1-6alkyl, -NRmRn, -OC(=O)R32or -C(=O)OC1-6alkyl; R32and R33are independently -OC1-6alkyl or C1-6alkyl substituted with one or more -NRmRn; R22, R23, Rmand Rnare independently hydrogen, C1-6alkyl or Boc. In a certain embodiment, the nitrogen-containing heterocyclic compound of formula I, the pharmaceutically acceptable salt thereof, a prodrug thereof, a stereoisomer thereof, a tautomer thereof or an isotopically labeled compound thereof as described above, wherein, represents a single or double bond; is phenyl, “5- to 7-membered heterocycloalkenyl containing 1–3 heteroatoms independently selected from O, S and N” or “5- to 7-membered heteroaryl containing 1–3 heteroatoms independently selected from O, S and N”; wherein D1is C, CH or N; D2is , wherein Z1and Z2are independently a bond, CH, CH2, O, S, N or NH; r is 0, 1 or 2; R5is independently halogen, C1-6alkyl, C1-6alkyl substituted with one or more halogen, hydroxyl, C1-6alkyl-O-, C2-6alkenyl or nitro; Y1is O, NH, CH2or Y2is NR2or O; m1, m2 and n are independently 0, 1, 2, 3 or 4; X1and X2are N; R1is C6-20aryl, “5- to 12-membered heteroaryl containing 1–4 heteroatoms independently selected from O, S and N”, C6-20aryl substituted with one or more R1-1or “5- to 12-membered heteroaryl containing 1–4 heteroatoms independently selected from O, S and N” substituted with one or more R1-2; provided that when multiple substituents are present, the substituents are the same or different; R1-1and R1-2are independently halogen, -ORc, cyano, -NR12R13, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -B(ORx) (ORy) or C1-6alkyl substituted by one or more R1-1-1; provided that when multiple substituents are present, the substituents are the same or different; R2, Rc, R12and R13are independently hydrogen, C1-6alkyl, -C(=O)Rc1, -C(=O)ORc2, - C(=O)NRc3Rc4, -SO2Rc5, , or C1-6alkyl substituted with one or more Rc10; Rc1, Rc2, Rc3, Rc4, Rc5, Rc6, Rc7, Rc8and Rc9are independently hydrogen, C1-20alkyl, C3-10cycloalkyl, C1-20alkyl substituted with one or more R4-1-1, C6-20aryl substituted with one or more R4-1-4, “5- to 7-membered heteroaryl containing 1 or 2 heteroatoms independently selected from O, S and N” , “5- to 7-membered heteroaryl containing 1 or 2 heteroatoms independently selected from O, S and N” substituted with one or more R4-1-5, -NRc51Rc52, -(C1-6alkylene-O)p-C1-6alkyl, ; p is 1, 2, 3 or 4; provided that when multiple substituents are present, the substituents are the same or different; R1-1-1, R4-1-1, R4-1-4and R4-1-5are independently halogen, hydroxyl, C1-6alkyl-O-, C1-6alkyl substituted with one or more R31, “4- to 7-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O, S, and N”, C6-20aryl, -C(=O)R21, -NR22R23, -C(=O)OR24, - OC(=O)R32, -COOH, -C(=O)OR27or -OC(=O)OR28; Rc10is -OC1-6alkyl, hydroxyl, substituted with C1-6alkyl, C6-20aryl substituted with one or more -B(ORx)(ORy), “5- to 7-membered heteroaryl containing 1 or 2 heteroatoms independently selected from O, S, and N” substituted with one or more Rc10-1,or -OC(=O)R29; Rc10-1 is independently C1-6alkyl or nitro; or, optional R2and R5together with the atoms to which they are attached, independently form “5- to 12-membered heterocyclic alkenyl containing 2 to 4 heteroatoms, two of which are N, and the other heteroatoms independently selected from O, S, and N”; Rxand Ryare independently hydrogen or C1-6alkyl, or Rxand Ryeach with the attached oxygen atom form five-membered ring substituted with one or more C1-6alkyl; R4is independently deuterium, halogen, hydroxyl, C1-6alkyl, O= or -C(=O)R4a; or, when n is 2, 3 or 4, two optional R4are connected, together with the atoms to which they are attached form “4- to 8-membered heterocyclic ring containing 1 to 3 heteroatoms independently selected from O, S, and N” substituted with one or more R4-5; R4-5is O=; R4ais C1-6alkyl or C2-6alkenyl; L1is a bond or -O(RL-1)n1-; RL-1is C1-6alkylene or C1-6alkylene substituted with one or more deuterium ; n1 is 1; R3is C3-12cycloalkyl substituted with one or more R3-1, “4- to 12-membered heterocycloalkyl containing 1–3 heteroatoms independently selected from O, S and N”, “4- to 12-membered heterocycloalkyl containing 1–3 heteroatoms independently selected from O, S and N” substituted with one or more R3-2or C2-6alkenyl substituted with one or more R3-4; provided that when multiple substituents are present, the substituents are the same or different; R3-1, R3-2and R3-4are independently C1-6alkyl, C1-6alkyl substituted with one or more R3-1-1, C6-20aryl substituted with one or more R3-1-5, Ar, C1-6alkyl-O-, -CH2-O-Ar, halogen orAr is “5- 12-membered heteroaryl containing 1-3 heteroatoms independently selected from O, N and S” substituted with one or more R3-1-4; R3-1-1, R3-1-5and R3-1-4are independently halogen, C1-6alkyl, C2-6alkenyl, C1-6alkyl-O- substituted with one or more halogen, C1-6alkyl substituted with one or more halogen, -C(=O)Re9, -NRe10Re11, -OC(=O)NRe15Re16, “4- to 10-membered heterocycloalkyl containing 1–3 heteroatoms independently selected from O, S and N”, or , “4- to 10-membered heterocycloalkyl containing 1–3 heteroatoms independently selected from O, S and N” substituted with one or more R3-1-1-1; or, two optional R3-1-5are connected, together with the atoms to which they are attached form “4- to 10-membered heterocycloalkyl containing 1–3 heteroatoms independently selected from O, S and N” substituted with one or more R3-1-1-2; R3-1-1-1and R3-1-1-2are independently, halogen,C1-6 alkyl or C6-20 aryl substituted with one or more R3-1-1-1-1; R3-1-1-1-1is independently halogen or C1-6alkyl substituted with one or more halogen; or, R3-1and R3-2are independently -L2-M; L2is -L21-L22-L23-L24-L25-L26; L21, L23and L25are independently a bond, O, S, NH, C(O)NH or C1-6alkylene; L22and L24are independently a bond, C3-10cycloalkyl, “4- to 7-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O, S and N”, C6-20aryl, or , “5- to 7-membered heteroaryl containing 1 or 2 heteroatoms independently selected from O, S, and N”; L26is a bond, O, S, NH or C(O)NH; Re17and Re18are independentlyhydrogen or halogen; Re9, Re10, Re11, Re15and Re16are independently hydrogen or C1-6alkyl; or, Rc3and Rc4together with the atom N to which they are attached form “4- to 12-membered heterocycloalkyl containing 1–3 heteroatoms, of which one is N, the other independently selected from O, S and N”, or , “4- to 12-membered heterocycloalkyl containing 1–3 heteroatoms, of which one is N, the other independently selected from O, S and N” substituted with one or more R3-1-3; R3-1-3is independently C1-6alkyl substituted with one or more R33, “4- to 7-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O, S and N” or -C(=O)OR30; Rc51, Rc52, R24, R27, R28and R30are independently hydrogen or C1-6alkyl; R29is hydrogen, C1-6alkyl or -NRmRn; R31is hydrogen, C1-6alkyl, -OC1-6alkyl, -NRmRn, -OC(=O)R32or -C(=O)OC1-6alkyl; R32and R33are independently-OC1-6alkyl or C1-6alkyl substituted with one or more -NRmRn; R21, R22, R23, Rmand Rnare independentlyhydrogen, C1-6alkyl or Boc. In a certain embodiment, the nitrogen-containing heterocyclic compound of formula I, the pharmaceutically acceptable salt thereof, a prodrug thereof, a stereoisomer thereof, a tautomer thereof or an isotopically labeled compound thereof as described above, wherein, “ “ represents a single or double bond; is phenyl, “5- to 7-membered heterocycloalkenyl containing 1–3 heteroatoms independently selected from O, S and N” or “5- to 7-membered heteroaryl containing 1–3 heteroatoms independently selected from O, S and N”; wherein D1is C or N; D2is , wherein Z1and Z2are independently a bond, CH, CH2N or NH; r is 0, 1 or 2; R5is independently halogen, C1-6alkyl, C1-6alkyl substituted with one or more halogen, hydroxyl or C2-6alkenyl; Y1is O, NH, CH2or Y2is NR2or O; R2is hydrogen, C1-6alkyl, -C(=O)Rc1or -C(=O)ORc2; Rc1is C1-20alkyl substituted with one or more R4-1-1; Rc2is C1-6alkyl; R4-1-1is independently halogen; m1and m2 are independently 0 or 1; n is 0, 1 or 2; R4is halogen, hydroxyl or C1-6alkyl; X1and X2are N; R1is C6-20aryl, “5- to 12-membered heteroaryl containing 1–4 heteroatoms independently selected from O, S and N”, C6-20aryl substituted with one or more R1-1or “5- to 12-membered heteroaryl containing 1–4 heteroatoms independently selected from O, S and N” substituted with one or more R1-2; provided that when multiple substituents are present, the substituents are the same or different; R1-1and R1-2are independently halogen, -ORc, cyano, -NR12R13, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -B(ORx) (ORy) or C1-6alkyl substituted by one or more R1-1-1; provided that when multiple substituents are present, the substituents are the same or different; Rcis hydrogen, -C(=O)Rc1, -C(=O)NRc3Rc4or C1-6alkyl substituted with one or more Rc10; Rc10is independently -OC(=O)R29; R29is -NRmRn; Rmand Rnare C1-6alkyl; Rc1, Rc3and Rc4are independently hydrogen, C1-20alkyl, C3-10cycloalkyl, -(C1-6alkylene-O)p-C1-6alkyl, C1-20alkyl substituted with one or more R4-1-1or C6-20aryl substituted with one or more R4-1-4; p is 1, 2 or 3; R4-1-1is independently C1-6alkyl-O-, -C(=O)R21, -NR22R23, -COOH or “4- to 7-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O, S, and N”; R21is C1-6alkyl; R22and R23are independently hydrogen, C1-6alkyl or Boc; R4-1-4is halogen; or, Rc3and Rc4together with the atom N to which they are attached form “4- to 12-membered heterocycloalkyl containing 1–3 heteroatoms, of which one is N, the other independently selected from O, S and N”, or , “4- to 12-membered heterocycloalkyl containing 1–3 heteroatoms, of which one is N, the other independently selected from O, S and N” substituted with one or more R3-1-3; R3-1-3is independently C1-6alkyl substituted with one or more R33or “4- to 7-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O, S and N”; R33is independently -OC1-6alkyl; R12and R13are independently hydrogen; Rxand Ryare independently hydrogen; R1-1-1is halogen; L1is a bond or -O(RL-1)n1-; RL-1is C1-6alkylene or C1-6alkylene substituted with one or more deuterium; n1 is 1; R3is C3-12cycloalkyl substituted with one or more R3-1, “4- to 12-membered heterocycloalkyl containing 1–3 heteroatoms independently selected from O, S and N”, “4- to 12-membered heterocycloalkyl containing 1–3 heteroatoms independently selected from O, S and N” substituted with one or more R3-2or C2-6alkenyl substituted with one or more R3-4; provided that when multiple substituents are present, the substituents are the same or different; R3-1is independently C1-6alkyl substituted with one or more R3-1-1; R3-1-1is independently - NRe10Re11, “4- to 10-membered heterocycloalkyl containing 1–3 heteroatoms independently selected from O, S and N”, or , “4- to 10-membered heterocycloalkyl containing 1–3 heteroatoms independently selected from O, S and N” substituted with one or more R3-1-1-1; Re10and Re11are independently C1-6alkyl; R3-1-1-1is independently C1-6 alkyl or C6-20 aryl substituted with one or more R3-1-1-1-1; R3-1-1-1-1is independently halogen; R3-2is independently halogen,3-1-1 ,C1-6 alkyl,C1-6 alkyl substituted with one or more R ,Ar, -CH2-O-Ar or C6-20aryl substituted with one or more R3-1-5; Ar is “5-12-membered heteroaryl containing 1-3 heteroatoms independently selected from O, N and S” substituted with one or more R3-1-4; R3-1-1is halogen, C2-6alkenyl or -OC(=O)NRe15Re16; Re15and Re16are independently C1-6alkyl; R3-1-5and R3-1-4are independently C1-6alkyl, halogen, C1-6alkyl-O- substituted with one or more halogen or C1-6alkyl substituted with one or more halogen; or, two optional R3-1-5are connected, together with the atoms to which they are attached form “4- to 10-membered heterocycloalkyl containing 1–3 heteroatoms independently selected from O, S and N” substituted with one or more R3-1-1-2; R3-1-1-2is independently halogen; or, R3-1is -L2-M; L2is -L21-L22-L23-L24-L25-L26; L21, L23and L25are independently a bond, O, S, NH, C(O)NH or C1-6alkylene; L22and L24are independently a bond, C3-10cycloalkyl, “4- to 7-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O, S and N”, C6-20aryl, or , “5- to 7-membered heteroaryl containing 1 or 2 heteroatoms independently selected from O, S, and N”; L26is a bond, O, S, NH or C(O)NH; R3-4is independently halogen or C1-6alkyl substituted with one or more R3-1-1; R3-1-1is independently -NRe10Re11or “4- to 10-membered heterocycloalkyl containing 1–3 heteroatoms independently selected from O, S and N”; Re10and Re11are independently C1-6alkyl; Re17and Re18are independently hydrogen or halogen. In a certain embodiment, with regard to a nitrogen-containing heterocyclic compound of formula I, a pharmaceutically acceptable salt thereof, a prodrug thereof, a stereoisomer thereof, a tautomer thereof or an isotopically labeled compound thereof, some groups are as defined as follows, and the unmentioned group definitons are described in any one of the embodiments of the present disclosure (this content is hereinafter referred to simply as “in a certain embodiment”). In a certain embodiment, two R4on the same carbon atom form ; or, two R4optional form 3- to 8- membered carbonyl ring. In a certain embodiment, D1is C or N. In a certain embodiment, in D2, one of Z1and Z2is CH, CH2or N; the other one is a bond. In a certain embodiment, r is 0, 1 or 2. In a certain embodiment, R5is independently halogen, C1-6alkyl, C1-6alkyl substituted with one or more halogen, hydroxyl, C1-6alkyl-O-, C2-6alkenyl or nitro. In a certain embodiment, when r is 1, . In a certain embodiment, X1and X2are N. In a certain embodiment, R1-1is independently halogen, -ORc, C1-6alkyl, -NR12R13, C2-6alkynyl or C1-6alkyl substituted by one or more R1-1-1; provided that when multiple substituents are present, the substituents are the same or different; R1-1-1is independently halogen. In a certain embodiment, R1-2is independently halogen, cyano, C2-6alkenyl or -NR12R13. In a certain embodiment, R12and R13are independently hydrogen, -SO2Rc5or -C(=O)ORc2; Rc2is C1-6alkyl. In a certain embodiment, Rcis hydrogen, -C(=O)Rc1, -C(=O)ORc2, -C(=O)NRc3Rc4, -SO2Rc5, , or C alkyl substituted wc10 c10 1-6ith one or more R ; R is independently - OC1-6alkyl, substituted with C1-6alkyl, C6-20aryl substituted with one or more - B(ORx)(ORy), “5- to 7-membered heteroaryl containing 1 or 2 heteroatoms independently selected O from O, S, and N” substituted with one or more Rc10-1, or -OC(=O)R29; Rc10-1isindependently C1-6alkyl or nitro; Rc1, Rc2, Rc3, Rc4, Rc5, Rc6, Rc7, Rc8and Rc9are independently hydrogen, C1-20alkyl, C3-10cycloalkyl, C1-20alkyl substituted with one or more R4-1-1, C6-20aryl substituted with one or more R4-1-4, “5- to 7-membered heteroaryl containing 1 or 2 heteroatoms independently selected from O, S and N” , “5- to 7-membered heteroaryl containing 1 or 2 heteroatoms independently selected from O, S and N” substituted with one or more R4-1-5, - O NRc51Rc52, -(C1-6alkylene-O)p-C1-6alkyl, p is 1, 2,3 or 4; provided that when multiple substituents are present, the substituents are the same or different; R1-1-1, R4-1-1, R4-1-4and R4-1-5are independently halogen, hydroxyl, C1-6alkyl-O-, C1-6alkyl, C1-6alkyl substituted with one or more R31, “4- to 7-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O, S, and N”, C6-20aryl, “5- to 7-membered heteroaryl containing 1 or 2 heteroatoms independently selected from O, S and N”, -NR22R23, -C(=O)OR24, -OC(=O)R32, - COOH, -C(=O)OR27or -OC(=O)OR28; Rxand Ryare independently hydrogen, or Rxand Ryeach with the attached oxygen atom form five-membered ring substituted with one or more C1-6alkyl. In a certain embodiment, when p is more than 1, each C1-6alkylene is the same or different. In a certain embodiment, Rc3and Rc4together with the atom N to which they are attached form “4- to 12-membered heterocycloalkyl containing 1–3 heteroatoms, of which one is N, the other independently selected from O, S and N”, or, “4- to 12-membered heterocycloalkyl containing 1–3 heteroatoms, of which one is N, the other independently selected from O, S and N” substituted with one or more R3-1-3; R3-1-3is independently C1-6alkyl substituted with one or more R33, “4- to 7- membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O, S and N” or -C(=O)OR30; R30is hydrogen or C1-6alkyl; R33is independently-OC1-6alkyl or C1-6alkyl substituted with one or more -NRmRn; Rmand Rnare independently hydrogen, C1-6alkyl or Boc. In a certain embodiment, when R1is C6-20aryl substituted with one or more R1-1, the more is two or three. In a certain embodiment, Y1is O, NH, CH2or In a certain embodiment, m1, m2 and n are independently 0, 1 or 2. In a certain embodiment, Y2is O or NR2. In a certain embodiment, R2is hydrogen, C1-6alkyl, -C(=O)Rc1or -C(=O)ORc2; Rc1is C1-20alkyl or C1-20alkyl substituted with one or more R4-1-1; Rc2is C1-6alkyl or C1-6alkyl substituted with one or more R4-1-1; R4-1-1is independently halogen, C6-20aryl or -OC(=O)R24; or, optional R2and R5together with the atoms to which they are attached, independently form “5- to 12-membered heterocyclic alkenyl containing 2 to 4 heteroatoms, two of which are N, and the other heteroatoms independently selected from O, S, and N”. In a certain embodiment, in Rc1, R4-1-1is independently halogen. In a certain embodiment, in Rc2, R4-1-1is independently C6-20aryl or -OC(=O)R24. In a certain embodiment, R24is C1-6alkyl. In a certain embodiment, R4is independently halogen, hydroxyl, deuterium, -C(=O)R4a, O= or C1-6alkyl; R4ais C1-6alkyl or C2-6alkenyl. In a certain embodiment, L1is a bond or -O(RL-1)n1-; RL-1is C1-6alkylene or C1-6alkylene substituted with one or more deuterium; n1 is 1. In a certain embodiment, R3is C3-12cycloalkyl substituted with one or more R3-1, “4- to 12- membered heterocycloalkyl containing 1–3 heteroatoms independently selected from O, S and N”, “4- to 12-membered heterocycloalkyl containing 1–3 heteroatoms independently selected from O, S and N” substituted with one or more R3-2or C2-6alkenyl substituted with one or more R3-4; provided that when multiple substituents are present, the substituents are the same or different. In a certain embodiment, R3-1is independently C1-6alkyl substituted with one or more R3-1-1; R3-1-1is independently -NRe10Re11, “4- to 10-membered heterocycloalkyl containing 1–3 heteroatoms independently selected from O, S and N”, or , “4- to 10-membered heterocycloalkyl containing 1– 3 heteroatoms independently selected from O, S and N” substituted with one or more R3-1-1-1; Re10and Re11are independently C1-6alkyl; R3-1-1-1is independently,C1-6 alkyl or C6-20 arylith one or more R3- substituted w1-1-1-1; R3-1-1-1-1is independently halogen or C1-6alkyl substituted with one or more halogen; Re17and Re18are independently hydrogen or halogen; or, R3-1is -L2-M; L2is -L21-L22-L23-L24-L25-L26; L21, L23and L25are independently a bond, O, S, NH, C(O)NH or C1-6alkylene; L22and L24are independently a bond, C3-10cycloalkyl, “4- to 7-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O, S and N”, C6-20aryl, or , “5- to 7-membered heteroaryl containing 1 or 2 heteroatoms independently selected from O, S, and N”; L26is a bond, O, S, NH or C(O)NH; . In a certain embodiment, R3-2is independently halogen, C1-6alkyl, ,C1-6 alkyl substitutedwith one or more R3-1-1, Ar, -CH2-O-Ar or C6-20aryl substituted with one or more R3-1-5; Ar is “5- 12-membered heteroaryl containing 1-3 heteroatoms independently selected from O, N and S” substituted with one or more R3-1-4; R3-1-1is halogen, C2-6alkenyl or -OC(=O)NRe15Re16; Re15and Re16are independently C1-6alkyl; Re17and Re18are independently hydrogen or halogen; R3-1-5and R3-1-4are independently C1-6alkyl, halogen, C1-6alkyl-O- substituted with one or more halogen or C1-6alkyl substituted with one or more halogen; or, two optional R3-1-5are connected, together with the atoms to which they are attached form “4- to 10-membered heterocycloalkyl containing 1–3 heteroatoms independently selected from O, S and N” substituted with one or more R3-1-1-2; R3-1-1-2is independently halogen. In a certain embodiment, R3-4is independently halogen or C1-6alkyl substituted with one or more R3-1-1; R3-1-1is independently -NRe10Re11or “4- to 10-membered heterocycloalkyl containing 1–3 heteroatoms independently selected from O, S and N”; Re10and Re11are independently C1-6alkyl. In a certain embodiment, Re17and Re18are independently hydrogen or halogen. In a certain embodiment, when the definition of R5, Rb, R1-1, R1-2, R1-1-1, R1-1-2, R1-1-3, R1-1-4, R1-1-5, R1-1-6, R4-1-1, R4-1-2, R4-1-3, R4-1-4, R4-1-5, R4, R4-1, R4-2, R4-3, R4-4, R4-5, Ra, R3-1, R3-2, R3-3, R3-4, R3-1-1, R3-1-2, R3-1-3, R3-1-5, R3-1-4, R4g, R4h, Re17, Re18, R3-1-1-1and R3-1-1-1-1mentions halogen, the halogen is fluorine, chlorine, bromine or iodine. In a certain embodiment, when the definition of R1, R1-1, R1-2, Rc1, Rc2, Rc3, Rc4, Rc5, Rc6, Rc7, Rc8, Rc9, R1-1-1, R1-1-2, R1-1-3, R1-1-4, R1-1-5, R1-1-6, R4-1-1, R4-1-2, R4-1-3, R4-1-4, R4-1-5, Rc10, R3-1, R3-2, R3-3, R3-4and R3-1-1-1mentions C6-20aryl, the C6-20aryl is phenyl or naphthyl. In a certain embodiment, when the definition of R5, R1-1, R1-2, R2, Rc, R12, R13, Rc10, Rc10-1, R1-1-1, R1-1-2, R1-1-3, R1-1-4, R1-1-5, R1-1-6, R4-1-1, R4-1-2, R4-1-3, R4-1-4, R4-1-5, Rc51, Rc52, R11, R21, R22, R23, R14, R24, R15, R25, R16, R26, R27, R28, R29, R30, R31, R32, R33, Rx, Ry, R4, R4-1, R4-2, R4-3, R4-4, R4-5, Ra, R4a, R4b1, R4b2, R4c, R4d1, R4d2, R4e, R4f1, R4f2, R4i, R4j, RL-3, R3, R3-1, R3-2, R3-3, R3-4, R4g, R4h, Re17, Re18, Rd, Rd1, Re1, Re2, Re3, Re4, R3-1-1, R3-1-2, R3-1-5, R3-1-4, R3-1-1-1, R3-1-1-1-1, Re5, Re6, Re7, Re8, Re9, Re10, Re11, Re12, Re13, Re14, Re15, Re16, Re171, Re172, Re173, Re174and R3-1-3mentions C1-6alkyl, the C1-6alkyl is C1-4alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert- butyl. In a certain embodiment, when the definition of Rc1, Rc2, Rc3, Rc4, Rc5, Rc6, Rc7, Rc8and Rc9independently is C1-20alkyl, the C1-20alkyl is C1-12alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl. In a certain embodiment, when the definition of R1-1, R1-2and R4mentions C2-6alkynyl, the C2-6alkynyl is C2-3alkynyl, for example, ethynyl, propynyl or propargyl. In a certain embodiment, when the definition of R5, R1-1, R1-2, R4, R4-1, R4-2, R4-3, R4-4, R4-5, Ra, R4a, R4b1, R4b2, R4c, R4d1, R4d2, R4e, R4f1, R4f2, R4i, R4j, R3, R3-1-1, R3-1-2, R3-1-5and R3-1-4mentions C2-6alkenyl, the C2-6alkenyl is C2-3alkenyl, for example, vinyl, propenyl or allyl. In a certain embodiment, when m1 is 0, m2 is 1, or m1 is 1, m2 is 0, n is 1 or 2. In a certain embodiment, when m1 and m2 are 1, n is 0. In a certain embodiment, when R1is “5- to 12-membered heteroaryl containing 1–4 heteroatoms independently selected from O, S and N” substituted with one or more R1-2, the “5- to 12-membered heteroaryl containing 1–4 heteroatoms independently selected from O, S and N” is “8- to 10- membered heteroaryl containing 1 heteroatom selected from O, S and N”, for example, benzothiophenyl. In a certain embodiment, when Ar is “5-12-membered heteroaryl containing 1-3 heteroatoms independently selected from O, N and S” substituted with one or more R3-1-4, the “5-12-membered heteroaryl containing 1-3 heteroatoms independently selected from O, N and S” is “5-10-membered heteroaryl containing 1-2 heteroatoms being N”, for example, pyridazinyl or pyrimidinyl. In a certain embodiment, when R3-1-1, R3-1-5and R3-1-4are independently C1-6alkyl substituted with one or more halogen, the C1-6alkyl substituted with one or more halogen is C1-2alkyl substituted with two or three fluorine. In a certain embodiment, R4is independently methyl, F, D, oxo, or hydroxyl. In a certain embodiment, or In a certain embodiment, R5is independently -F, -OH, -Cl, -CF3, , , -NO2, -OEt or -OMe, or, R2and R5form or In a certain embodiment, R1is F

[0002] In a certain embodiment, L1is a bond, -OCH2- or -OCD2-. In a certain embodiment, R3is

[0003] , , , , In a certain embodiment,

[0004] In a certain embodiment, the nitrogen-containing heterocyclic compound of formula I has any of the following structures:

[0005]  The present disclosure also provides a compound having any one of the following structures:

[0006] . The present disclosure also provides a pharmaceutical composition comprising a substance A and a pharmaceutically acceptable excipient, wherein the substance A is the compound containing structure of a nitrogen-containing heterocyclic compound of formula I, the pharmaceutically acceptable salt thereof, the prodrug therof, the stereoisomer thereof, the tautomer thereof or the isotopically labeled compound thereof as described above. The present disclosure also provides a method for inhibiting RAS in a subject in need thereof, comprising: administering a therapeutically effective amount of a substance A to the subject, wherein the substance A is the compound containing structure of a nitrogen-containing heterocyclic compound of formula I, the pharmaceutically acceptable salt thereof, the prodrug therof, the stereoisomer thereof, the tautomer thereof or the isotopically labeled compound thereof as described above. In the method for inhibiting RAS in a subject in need thereof, wherein the RAS is wild type RAS or mutated forms of RAS. The wild type RAS is wild-amplified KRAS. The mutated forms of RAS such as a KRAS, HRAS or NRAS mutation, wherein the mutated forms of KRAS can be mutated G12, G13 or Q61, for example, KRAS G12C, KRAS G12D, KRAS G12S, KRAS G12A, KRAS G12V or KRAS G13D, and for another example, KRAS G12C, KRAS G12D or KRAS G12V; the mutated forms of HRAS be mutated G12, G13 or Q61, for example, mutated HRAS G12C, HRAS G12D, HRAS G12S, HRAS G12A, HRAS G12V or HRAS G13D; the mutated forms of NRAS can be mutated G12, G13 or Q61, for example, NRAS G12C, NRAS G12D, NRAS G12S, NRAS G12A, NRAS G12V or NRAS G13D. The present disclosure also provides a method for treating or preventing a RAS-related disease in a subject in need thereof, comprising: administering a therapeutically effective amount of a substance A to the subject, wherein the substance A is the compound containing structure of the nitrogen- containing heterocyclic compound of formula I, the pharmaceutically acceptable salt thereof, the prodrug therof, the stereoisomer thereof, the tautomer thereof or the isotopically labeled compound thereof as described above. In the method for inhibiting RAS in a subject in need thereof, wherein the RAS is wild type RAS or mutated forms of RAS. The wild type RAS is wild-amplified KRAS. The mutated forms of RAS such as a KRAS, HRAS or NRAS mutation, wherein the mutated forms of KRAS can be mutated G12, G13 or Q61, for example, KRAS G12C, KRAS G12D, KRAS G12S, KRAS G12A, KRAS G12V or KRAS G13D, and for another example, KRAS G12C, KRAS G12D or KRAS G12V; the mutated forms of HRAS be mutated G12, G13 or Q61, for example, mutated HRAS G12C, HRAS G12D, HRAS G12S, HRAS G12A, HRAS G12V or HRAS G13D; the mutated forms of NRAS can be mutated G12, G13 or Q61, for example, NRAS G12C, NRAS G12D, NRAS G12S, NRAS G12A, NRAS G12V or NRAS G13D. In the method for treating or preventing a RAS-related disease in a subject in need thereof, wherein the RAS-related disease is cancer, the cancer is selected from the group consisting of colon cancer, appendiceal cancer, pancreatic cancer, MYH-related polyposis, hematologic cancer, breast cancer, endometrial cancer, gallbladder cancer, bile duct cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, cervical cancer, testicular cancer, kidney cancer, head or neck cancer, bone cancer, skin cancer, rectal cancer, liver cancer, esophageal cancer, stomach cancer, thyroid cancer, bladder cancer, lymphoma, leukemia and melanoma. The present disclosure also provides a method for treating or preventing cancer in a subject in need thereof, comprising: administering a therapeutically effective amount of a substance A to the subject, wherein the substance A is the compound containing structure of the nitrogen-containing heterocyclic compound of formula I, the pharmaceutically acceptable salt thereof, the prodrug therof, the stereoisomer thereof, the tautomer thereof or the isotopically labeled compound thereof as described above; the cancer is selected from the group consisting of colon cancer, appendiceal cancer, pancreatic cancer, MYH-related polyposis, hematologic cancer, breast cancer, endometrial cancer, gallbladder cancer, bile duct cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, cervical cancer, testicular cancer, kidney cancer, head or neck cancer, bone cancer, skin cancer, rectal cancer, liver cancer, esophageal cancer, stomach cancer, thyroid cancer, bladder cancer, lymphoma, leukemia and melanoma. The term “more” refers to 2, 3, 4 or 5. The term “pharmaceutically acceptable salt” refers to a salt of the compound disclosed herein which is prepared using relatively safe and pharmaceutically acceptable acids or bases. When the compound disclosed herein contains a relatively acidic functional group, a base addition salt can be obtained by contacting a neutral form of the compound with a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to: lithium salt, sodium salt, potassium salt, calcium salt, aluminum salt, magnesium salt, zinc salt, bismuth salt, ammonium salt, and diethanolamine salt. When the compound disclosed herein contains a relatively basic functional group, an acid addition salt can be obtained by contacting a neutral form of the compound with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent. The pharmaceutically acceptable acid includes inorganic acids, including, but not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, and sulfuric acid. The pharmaceutically acceptable acids include organic acids, including, but not limited to: acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acidic citric acid, oleic acid, tannic acid, pantothenic acid, bitartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, saccharic acid, formic acid, ethanesulfonic acid, pamoic acid (i.e., 4,4'-methylene-bis(3-hydroxyl-2-naphthoic acid)), and amino acids (e.g., glutamic acid and arginine). When a compound disclosed herein contains both relatively acidic functional group and relatively basic functional group, it can be converted to either base addition salt or acid addition salt. For details, see Berge et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science 66:1-19 (1977), or Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002). The term “stereoisomer” refers to isomers of a molecule having the same order of atoms or radicals but different spatial arrangement, such as cis-trans isomer, optical isomer or atropisomer. Such stereoisomers can be separated, purified and enriched by asymmetric synthesis or chiral resolution (including but not limited to thin layer chromatography, centrifugal partition chromatography, column chromatography, gas chromatography, and high pressure liquid chromatography), and can also be obtained by chiral resolution via bonding (chemical bonding, etc.) or salification (physical bonding, etc.) with other chiral compounds. The term “tautomer” refers to functional isomers of a molecule where an atom rapidly migrates between two positions. For example, acetone and 1-propen-2-ol can be mutually converted when hydrogen atom rapidly migrates between oxygen and α-carbon atoms. The term “isotopically labeled compound” refers to a compound where one or more atoms are replaced by one or more atoms having a specific atomic mass or mass number. Examples of isotope that can be incorporated into the compound disclosed herein include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, sulfur, and chlorine (e.g., 2H, 3H, 13C, 14C, 15N, 18O, 17O, 18F, 35S, and 36Cl). An isotopically labeled compound of the present disclosure can generally be prepared by replacing a non-isotopically labeled reagent with an isotopically labeled reagent according to the methods described herein. The term “halogen” refers to fluorine, chlorine, bromine or iodine. The term “alkyl” refers to a linear or branched alkyl group having a specified number of carbon atoms. Examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. The term “alkylene” refers to a linking group between two other species, which may be linear or branched. Examples include, but are not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2CH(CH3)- and -CH2CH(CH2CH3)CH2-. The term “alkoxy” refers to the group -O-RX, wherein RXis an alkyl as defined above. The terms “cycloalkyl” and “carbocyclic ring” refer to a saturated cyclic group consisting only of carbon atoms having a specified number of carbon atoms (e.g., C3–C6), which is a monocyclic, bridged or spiro ring. The cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The term “aryl” refers to an aromatic group consisting of carbon atoms, each ring having aromaticity. For example, phenyl or naphthyl. The term “heteroaryl” refers to a cyclic group having a specified number of ring atoms (e.g., 5–12 members), a specified number of heteroatoms (e.g., 1, 2, or 3) and specified heteroatom species (one or more of N, O and S), which is monocyclic or polycyclic, and has at least one aromatic ring (according to the Hückel's rule). Heteroaryls are linked to other fragments of the molecule through aromatic or non-aromatic rings. Heteroaryls include, but are not limited to, furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, and indolyl. The terms “heterocyclyl”, “heterocycle” or “heterocycloalkyl” refer to a cyclic group having a specified number of ring atoms (e.g., 3–8 members), a specified number of heteroatoms (e.g., 1, 2, or 3) and specified heteroatom species (one or more of N, O and S), which is monocyclic, bridged, or spiro, and where each ring is saturated. Heterocycloalkyls include, but are not limited to, azetidinyl, tetrahydropyrrolyl, tetrahydrofuryl, morpholinyl, piperidinyl, and the like. The term “hydroxyl” refers to a -OH group. The term “cyano” refers to a -CN group. The term “oxo” refers to a =O group. Unless otherwise specified, is referred as two hydrogens on the same carbon are substituted with, for example, when the two hydrogens are substituted with , forming a structure of . The same is for definition Substituted “Cx1–Cy1” groups with specified numbers of carbon atoms (x1 and y1 are integers), for example, “Cx1–Cy1” alkyl, “Cx1–Cy1” cycloalkyl, “Cx1–Cy1” cycloalkenyl, “Cx1–Cy1” alkoxyl, “Cx1– Cy1” alkenyl,”Cx1–Cy1” alkynyl, “Cx1–Cy1”aryl, “Cx1–Cy1” heteroaryl, or “Cx1–Cy1” heterocyclyl, all represent numbers of carbon atoms excluding substituents, e.g., a C1–C6alkyl represents a C1–C6alkyl excluding substituents. In the present disclosure, when R12and R13, R15and R16, Rc3and Rc4, R22and R23, R25and R26, R4b1and R4b2, R4d1and R4d2, R4f1and R4f2, R4iand R4j, Re1and Re2, Re3and Re4, Re5and Re6, Re7and Re8, Re10and Re11, Re13and Re14, Re15and Re16, Re173and Re174together with the atom N to which they are attached form “4- to 12-membered heterocycloalkyl containing 1–3 heteroatoms, of which one is N, the other independently selected from O, S and N”, or , “4- to 12-membered heterocycloalkyl containing 1–3 heteroatoms, of which one is N, the other independently selected from O, S and N” substituted with one or more R3-1-3; the combination of heteroatoms in the “4- to 12-membered heterocycloalkyl containing 1–3 heteroatoms, of which one is N, the other independently selected from O, S and N” and “4- to 12-membered heterocycloalkyl containing 1–3 heteroatoms, of which one is N, the other independently selected from O, S and N” substituted with one or more R3-1-3is (N), (N and O), (N and S) or (N, O and S). The above preferred conditions may be combined arbitrarily to obtain preferred embodiments of the present disclosure without departing from the general knowledge in the art. The reagents and starting materials used in the present disclosure are commercially available. The positive / progressive effects of the present disclosure are as follows: The nitrogen-containing heterocyclic compounds as represented in Formula I in the present invention have good inhibitory effects on cells of various mutations such as KRAS G12C, KRAS G12D, KRAS G12V, KRAS Q61H and other mutations, as well as on KRAS-amplified wild-type cells, and are expected to treat and / or prevent a wide range of diseases associated with Ras. Detailed description of the embodiments The present disclosure is further illustrated by the following examples, which are not intended to limit the present disclosure. Experimental procedures without specified conditions in the following examples were performed in accordance with conventional procedures and conditions, or in accordance with instructions. The solvents involved in the following embodiment are all analytical or chromatographic pure.In the examples below, the ratio of solvents is by volume, if not otherwise specified. In the present disclosure, room temperature refers to ambient temperature, or 10–35 °C. Overnight refers to 8–15 hours. Reflux refers to the reflux temperature of a solvent at atmospheric pressure. The following is a list of abbreviations used in the examples: DMF N, N-dimethylformamide DMAc N, N-dimethylacetamide DIPEA diisopropylethylamine TIPS Triisopropylsilyl THF Tetrahydrofuran MOM Methoxymethyl DCM dichloromethane EA ethyl acetate DMSO dimethyl sulfoxide PE petrol ether MeOH methanol cataCXium A Pd G3 [n-Butylbis(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium methanesulfonate (II) Pd(DPEphos)Cl2Bis(diphenylphosphine phenyl ether)palladium(II) chloride PdCl2(dtbpf) Dichloro[1,1'-bis(di-tert-butylphosphino)ferrocene]palladium (II) DABCO 1,4-Diazabicyclo[2.2.2]octane Pd(dppf)Cl2[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride Pd2(dba)3tris(dibenzylideneacetone)dipalladium TFA Trifluoroacetic acid Boc tert-butoxycarbonyl Cbz benzyloxycarbonyl NBS N-Bromosuccinimide TMSOTf Trimethylsilyl trifluoromethanesulfonate TBSOTf tert-Butyldimethylsilyl trifluoromethanesulfonate Example 1 Synthetic route of compound 1

[0007] Synthesis of compound 1-j To a reaction vial were added 2-(tert-butyl)hydrazine-1,2-dicarboxylic acid-1-benzyl ester (1000 mg, 3.76 mmol) and DMF (10 mL) at room temperature. After degassed and purged with nitrogen, and cooled in an ice-water bath under protection of nitrogen, the above mixture was added NaH (60%, 376 mg, 9.40 mmol) in batches. After stirred for 5 min after addition, the resulting mixture was added 3-bromopropene (1000 mg, 8.27 mmol) slowly dropwise over half an hour. After completion of the addition, the reaction mixture was warmed to room temperature naturally and stirred for another 3 hours. The reaction mixture was added 100 mL of water and 100 mL of ethyl acetate, partitioned and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with water, dried and concentrated to obtain compound 1-j (1200 mg, 92%). LC- MS (ESI): m / z 247.2 (M-Boc+H)+. Synthesis of compound 1-i To a reaction vial were added 1-j (1200 mg, 3.46 mmol), DCM (180 mL) , phenylmethylenebis(tricyclohexylphosphine) ruthenium dichloride (285 mg, 0.35 mmol) at room temperature. The reaction mixture was degassed and purged with nitrogen, stirred at 45°C overnight. The reaction mixture was concentrated and the residue was purified by column chromatography (mobile phase: PE / EA 10 / 0 to 10 / 1) to give compound 1-i (970 mg, 88%). LC-MS (ESI): m / z 219.1 (M-Boc+H)+. Synthesis of compounds 1-h 1-i (970 mg, 3.05 mmol) and THF (10 mL) were added to a reaction vial at room temperature. After degassed and purged with nitrogen, and cooled in an ice-water bath, the above mixture was added a solution of borane (1M, 10 mL, 10.00 mmol) in tetrahydrofuran dropwise, then stirred at room temperature overnight after the dropwise addition. Hydrogen peroxide (30 wt%, 10 mL) was added dropwise, NaOH (61 mg, 1.53 mmol) was added and the resulting mixture was stirred for 1 hour. The reaction mixture was concentrated at room temperature at reduced pressure to remove tetrahydrofuran, extracted by adding DCM, and the organic phase was dried over anhydrous sodium sulfate, concentrated, and the residue was purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to give compound 1-h (910 mg, 89%). LC-MS (ESI): m / z 236.9 (M-Boc+H)+. Synthesis of compound 1-g At room temperature, to a reaction vial were added 1-h (900 mg, 2.68 mmol), DCM (20 mL), and Days-Martin reagent (2837 mg, 6.69 mmol). After degassed and purged with nitrogen, the reaction mixture was stirred at room temperature overnight. The reaction mixture was added 100 mL of dichloromethane, washed with saturated aqueous sodium bicarbonate first, then saturated aqueous sodium bisulfite, washed with water, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by column chromatography (mobile phase: PE / EA 10 / 0 to 4 / 6) to give compound 1-g (700 mg, 78%). LC-MS (ESI): m / z 235.1 (M-Boc+H)+. Synthesis of compound 1-f A solution of methylmagnesium bromide (1M, 8.2 mL, 8.20 mmol) in Tetrahydrofuran and THF (10 mL) were added to a reaction flask at room temperature. After degassed and purged with nitrogen and cooled in an ice-water bath, the above mixture was added a solution of 1-g (2100 mg, 6.28 mmol) in THF (10 mL) dropwise. Stirred for 2 hours at room temperature after dropwise addition, the reaction mixture was quenched by pouring into saturated aqueous ammonium chloride solution, extracted with DCM. The organic phase was washed with water, dried over anhydrous sodium sulfate, concentrated and the residue was purified by column chromatography (mobile phase: PE / EA 10 / 0 to 5 / 5) to give compound 1-f (1500 mg, 68%). LC-MS (ESI): m / z 251.2 (M-Boc+H)+. Synthesis of compounds 1-e-1, 1-e-2 1-f (700 mg, 2.00 mmol) and acetonitrile (20 mL) were added to a reaction flask at room temperature. After degassed and purged with nitrogen and cooled in an ice-water bath, the above mixture was added HCl / 1,4-dioxane (1M, 4mL, 4.00 mmol). The reaction mixture was stirred for 5 hours at room temperature. The reaction mixture was concentrated, made basic by adding a solution of ammonia in methanol (7 M) and concentrated. Water was added and the aqueous phase was extracted with a mixed solution of DCM:MeOH=10:1. The organic phase was dried over anhydrous sodium sulfate, concentrated, and the residue was purified by prep-HPLC (mobile phase: water (0.01 M NH4HCO3) / acetonitrile 10 / 0 to 7 / 3) to give compounds 1-e-1 (250 mg, 50%) and 1-e-2 (180 mg, 36%). Compound 1-e-1（250mg，50%）. LC-MS (ESI): m / z 251.2 (M+H)+;1H NMR (400MHz, CDCl3): δ 7.43-7.30 (5H, m), 5.22(2H, s), 3.82 (1H, d, J = 12.0Hz), 3.28 -3.14 (2H, m), 2.95-2.86 (1H, m), 1.76-1.64 (2H, m), 1.26(3H, s). Compound 1-e-2（180mg，36%）. LC-MS (ESI): m / z 251.2 (M+H)+;1H NMR (400MHz, CDCl3): δ 7.45-7.31 (5H, m), 5.20(2H, s), 4.05 (1H, d, J = 13.2Hz), 3.45 -3.25 (1H, m), 2.87-2.70 (2H, m), 1.70-1.60 (2H, m), 1.23(3H, s). Synthesis of compounds 1-d To a reaction vial were added 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (303 mg, 1.20 mmol), DCM (15 mL) at room temperature. After degassed and purged with nitrogen, the above mixture was cooled to -78°C, was added DIPEA (258 mg, 2.00 mmol) and a solution of 1-e-1 (250 mg, 1.00 mmol) in THF (5 mL) dropwise. After addition, the reaction mixture was naturally warmed to room temperature overnight. The reaction mixture was added with water, and the aqueous phase was extracted with DCM. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by column chromatography (mobile phase: PE / EA 10 / 0 to 6 / 4) to give compound 1-d (300 mg, 64%). LC-MS (ESI): m / z 466.5 (M+H)+. Synthesis of compounds 1-c To a reaction vial were added 1-d (300 mg, 0.64 mmol), ((2R,7aS)-2-fluorohexahydro-1H- pyrrolizin-7a-yl)methanol (123 mg, 0.77 mmol), 1,4-dioxane (7 mL), DIPEA (208 mg, 1.61 mmol) at room temperature. After degassed and purged with nitrogen, the reaction mixture was stirred at 90°C overnight. The reaction mixture was concentrated and the residue was purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to give compound 1-c (290 mg, 77%). LC-MS (ESI): m / z 589.6 (M+H)+. Synthesis of compound 1-b At room temperature, to a microwave tube were added 1-c (200 mg, 0.34 mmol), 2-(8-ethyl-7- fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (148 mg, 0.41 mmol), cataCXium A Pd G3 (22 mg, 0.03 mmol) , potassium phosphate (217 mg, 1.02 mmol), 1,4-dioxane (2 mL), and water (0.5 mL). The mixture was degassed and purged with nitrogen, sealed, and stirred at 80 °C overnight. The reaction mixture was concentrated and the residue was purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to give compound 1-b (140 mg, 52%). LC-MS (ESI): m / z 787.2 (M+H)+. Synthesis of compound 1-a To a reaction vial were added 1-b (140 mg, 0.18 mmol) and acetonitrile (5 mL) at room temperature. After degassed and purged with nitrogen, the above mixture was cooled down to 0 °C, was added HCl / 1,4-dioxane (4.0 M, 1 mL). It was stirred at 0°C for 3 hours. The reaction mixture was concentrated at low temperature to give the crude compound 1-a (132 mg). LC-MS (ESI): m / z 743.7 (M+H)+. Synthesis of compound 1 At room temperature, to a reaction vial were added crude compound 1-a (132 mg, 0.18 mmol), methanol (13 mL), Pd / C 10% (130 mg). After degassed and purged with H2, and stirred at room temperature overnight. The reaction mixture was filtered, and the filtrate was concentrated and the residue was purified by column chromatography (mobile phase: DCM / MeOH(NH3) 10 / 0 to 10 / 1) to give compound 1 (49 mg, 45%). LC-MS (ESI): m / z 609.7 (M+H)+. Synthesis of compounds 1-1 and 1-2 Compound 1（39 mg，0.064 mmol）was separated by chiral resolution to obtain compound 1-1 （16 mg，41%），LC-MS (ESI): m / z 609.6 (M+H)+；compound 1-2（15 mg，38%），LC-MS (ESI): m / z 609.6 (M+H)+.

[0008] Example 2 Synthetic route of compound 2 Synthesis of compounds 2-d At room temperature, to a reaction vial were added 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (217 mg, 0.86 mmol) and DCM (15 mL). After degassed and purged with nitrogen, the above mixture was cooled to -78°C, was added DIPEA (186 mg, 1.44 mmol) and a solution of 1-e-2 (180 mg, 0.72 mmol) in THF (5 mL) dropwise. After addition, the reaction mixture was naturally warmed to room temperature and stirred overnight. The reaction mixture was added with water, and the aqueous phase was extracted with DCM. The organic phases were combined, dried, concentrated, and the residue was purified by column chromatography (mobile phase: PE / EA 10 / 0 to 6 / 4) to give compound 2-d (200 mg, 60%). LC-MS (ESI): m / z 466.5 (M+H)+. Synthesis of compound 2-c At room temperature, to a reaction vial were added 2-d (200 mg, 0.43 mmol), ((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methanol (82 mg, 0.52 mmol), 1,4-dioxane (6 mL) and DIPEA (138 mg, 1.07 mmol). After degassed and purged with nitrogen, the reaction mixture was stirred at 90°C overnight. The reaction mixture was concentrated and the residue was purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to give compound 2-c (230 mg, 91%). LC-MS (ESI): m / z 589.6 (M+H)+. Synthesis of compound 2-b At room temperature, to a microwave tube were added 2-c (230 mg, 0.39 mmol), 2-(8-ethyl-7- fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (169 mg, 0.47 mmol), cataCXium A Pd G3 (29 mg, 0.04 mmol) , potassium phosphate (248 mg, 1.17 mmol), 1,4-dioxane (2 mL) and water (0.5 mL). The mixture was degassed and purged with nitrogen, sealed, and stirred at 80 °C overnight. The reaction mixture was concentrated and the residue was purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to give compound 2-b (220 mg, 72%). LC-MS (ESI): m / z 787.7 (M+H)+. Synthesis of compound 2-a At room temperature, to a reaction vial were added 2-b (220 mg, 0.28 mmol), acetonitrile (5 mL). After degassed and purged with nitrogen, the above mixture was cooled down to 0 °C and was added HCl / 1,4-dioxane (4.0 M, 1 mL). It was stirred at 0°C for 3 hours. The reaction mixture was concentrated at low temperature to give the crude compound 2-a (208 mg). LC-MS (ESI): m / z 743.7 (M+H)+. Synthesis of compound 2 At room temperature, to a reaction vial were added crude compound 2-a (208 mg, 0.28 mmol), methanol (20 mL) and Pd / C 10% (200 mg). After degassed and purged with H2, the reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered, and the filtrate was concentrated, and the residue was purified by column chromatography (mobile phase: DCM / MeOH(NH3) 10 / 0 to 10 / 1) to give compound 2 (93 mg, 55%). LC-MS (ESI): m / z 609.7 (M+H)+. Synthesis of compounds 2-1&2-2 Compound 2（79 mg，0.13 mmol）was separated by chiral resolution to obtain compound 2-1（27 mg，34%），LC-MS (ESI): m / z 609.6 (M+H)+;1H NMR (400MHz, DMSO-d6): δ 10.39-10.29 (1H, d, J =7.2 Hz), 9.92 (1H, s), 7.81-7.71 (1H, dd, J =8.8, 6.0 Hz), 7.40-7.28 (2H, m), 7.06-6.94 (1H, m), 5.55-5.40 (1H, m), 5.41-5.18 (1H, d, J =54.4 Hz), 4.91-4.74(1H, m), 4.27-3.91 (2H, m), 3.30- 2.94 (5H, m), 2.92-2.57 (2H, m), 2.44-1.95 (6H, m), 1.94-1.57 (5H, m), 1.27-1.14 (3H, m), 0.80- 0.64 (3H, t, J =7.2 Hz); compound 2-2（28 mg，35%），LC-MS (ESI): m / z 609.6 (M+H)+. Example 3 Synthetic route of compound 3

[0009] Synthesis of compounds 3-c To a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (300 mg, 1.19 mmol) in dichloromethane (30 mL) was added tert-butyl 1,2-diazepine-1-carboxylate (238 mg, 1.19 mmol) and N,N-diisopropylethylamine (461 mg, 3.56 mmol) in a a dry ice-acetone bath, and the mixture was stirred for 1 hour at this temperature. The reaction mixture was warmed to room temperature and continued stirring for 1 h. Water was added and the aqueous phase was extracted with dichloromethane (50 mL*2), the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to dryness to give compound 3-c (490 mg, 99%). LC-MS (ESI): m / z 416.0 (M+H)+. Synthesis of compound 3-b To a solution of 3-c (490 mg, 1.18 mmol) in dichloromethane (20 mL) was added ((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methanol (281 mg, 1.77 mmol) in an ice-water bath and followed by slow addition of sodium tert-butoxide (226 mg, 2.35 mmol) and the mixture was stirred for 2 h at this temperature. Then water was added to the mixture and the aqueous phase was extracted with dichloromethane (50 mL*2), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness and the crude was purified by flash column chromatography (mobile phase: dichloromethane: methanol=10:1 / dichloromethane, 0-50%) to give compound 3-b (561 mg, 88%). LC-MS (ESI): m / z 539.4 (M+H)+. Synthesis of compound 3-a To a 10 mL microwave tube were added 3-b (70 mg, 0.13 mmol), 2-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (70 mg, 0.20 mmol), methanesulfonicacid[n-butylbis(1-adamantyl)phosphine](2-amino-1,1'- biphenyl-2-yl)palladium(II) (9 mg, 0.013 mmol), potassium phosphate (83 mg, 0.39 mmol), tetrahydrofuran (5 mL) and water (1 mL). After degassed and purged with nitrogen several times, the microwave tube was sealed. The reaction mixture was stirred at 65 °C overnight. Water was added to the reaction mixture and the aqueous phase was extracted with ethyl acetate (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness and the crude was purified by flash column chromatography (mobile phase: methanol / dichloromethane, 0-100%) to give compound 3-a (74 mg, 77%). LC-MS (ESI): m / z 737.8 (M+H)+. Synthesis of compound 3 To a solution of 3-a (74 mg, 0.1 mmol) in acetonitrile (15 mL) was added HCl / 1,4-dioxane (4M, 3 mL)in an ice-water bath. The temperature was slowly warmed to room temperature and the mixture was stirred at this temperature overnight. Saturated aqueous sodium bicarbonate solution was added and the aqueous phase was extracted with ethyl acetate (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness and the crude was purified by prep-HPLC to give compound 3 (13.5 mg, 23%). LC-MS (ESI): m / z 593.3 (M+H)+. Example 4 Synthetic route of compound 4 Synthesis of compound 4-b To a microwave tube (30 mL) were added 3-b (150 mg, 0.28 mmol), ((2-fluoro-6- (methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1- yl)ethynyl)triisopropylsilane (171 mg, 0.33 mmol), methanesulfonato[n-butylbis(1-adamantyl) phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (20 mg, 0.028 mmol), potassium phosphate (177 mg, 0.83 mmol), tetrahydrofuran (15 mL) and water (3 mL). The microwave tube was sealed, degassed and purged with nitrogen several times and stirred at 65 °C overnight. The reaction mixture was added water, extracted with ethyl acetate (50mL*2), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness and the crude was purified by flash column chromatography (mobile phase: methanol / dichloromethane, 0-20%) to obtain 4-b (244mg, 99%). LC-MS (ESI): m / z 889.9 (M+H)+. Synthesis of compound 4-a Cesium fluoride (417 mg, 2.74 mmol) was added to a solution of 4-b (244 mg, 0.27 mmol) in N,N- dimethylformamide (10 mL) at room temperature and the mixture was stirred for 1 h at room temperature. Water was added and the aqueous phase was extracted with ethyl acetate (50 mL*2), the combined organic phases were washed twice with water and twice with brine sequentially, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to give compound 4-a (200 mg, 99%). LC-MS (ESI): m / z 733.8 (M+H)+. Synthesis of compound 4 To a solution of 4-a (200 mg, 0.27 mmol) in acetonitrile (15 mL) was added HCl / 1,4-dioxane (4M, 5 mL)in an ice-water bath. The mixture was slowly warmed to room temperature and stirred at this temperature overnight. The reaction mixture was added saturated aqueous sodium bicarbonate solution and the aqueous phase was extracted with ethyl acetate (30 mL*2), the combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and the crude was purified by prep-HPLC to give compound 4 (120 mg, 75%). LC-MS (ESI): m / z 589.3 (M+H)+;1H NMR (400 MHz, CDCl3): δ 10.15 (1H, d, J = 34.8 Hz), 7.55-7.46 (1H, m), 7.25 (1H, dd, J = 38.4, 1.6 Hz), 7.15-7.07 (1H, m), 7.02 (1H, s), 5.31 (1H, d, J = 54.0 Hz), 4.43-4.31 (1H, m), 4.30 – 4.16 (2H, m), 4.06 – 3.92 (2H, m), 3.41 – 3.07 (4H, m), 3.06 – 2.96 (2H, m), 2.79 (1H, d, J = 4.4 Hz), 2.46 – 2.10 (4H, m), 2.03 – 1.85 (4H, m), 1.78 – 1.57 (4H, m). Example 5 Synthetic route of compound 5 Synthesis of compound 5 To a solution of compound 4 (20 mg, 0.034 mmol) in dichloromethane (8 mL) was slowly added acetyl chloride (13 mg, 0.17 mmol) and N,N-diisopropylethylamine (44 mg, 0.34 mmol) in an ice- water bath, and the mixture was stirred for 2 hr at 0°C. The mixture was concentrated to dryness, dissolved in methanol (6 mL), was added potassium carbonate (94 mg, 0.68 mmol) and the mixture was stirred for 2 hours at room temperature. To the reaction mixture, water was added and the aqueous phase was extracted with ethyl acetate (30 mL*2), the combined organic phases were dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness and the crude was purified by prep-HPLC to give compound 5 (8.8 mg, 41%). LC-MS (ESI): m / z 631.3 (M+H)+. Example 6 Synthetic route of compound 6 Synthesis of compound 6-f A reaction vial charged with tert-butyl 1,2-diazepane-1-carboxylate (200 mg, 0.999 mmol), methanol (20 mL), paraformaldehyde (270 mg, 2.997 mmol), and sodium cyanoborohydride (188 mg, 2.996 mmol) was stirred at room temperature overnight under atmosphere of nitrogen.The next day, the reaction mixture was concentrated to dryness and the residue was purified by column chromatography (mobile phase: ethyl acetate / petroleum ether 0 / 100 to 20 / 80) to give compound 6- f (189 mg, 88%). LC-MS (ESI): m / z = 215.2 (M+H)+. Synthesis of compound 6-e To a reaction vial were added 6-f (188 mg, 0.877 mmol), acetonitrile (20 mL) and hydrochloric acid / 1,4-dioxane (4 M, 2 mL), and the mixture was stirred at room temperature overnight under atmosphere of nitrogen.The next day, the reaction mixture was directly concentrated to dryness to give compound 6-e (132 mg, 99.9%), which was used directly for the next step without purification. LC-MS (ESI): m / z = 115.2 (M+H)+. Synthesis of compound 6-d To a reaction vial were added 6-e (140 mg, 0.929 mmol), dichloromethane (30 mL), diisopropylethylamine (0.461 mL, 2.788 mmol). Cooled in a dry ice-acetone bath, the above mixture was added 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (235 mg, 0.929 mmol) and stirred for 1 hr under atmosphere of nitrogen. Quenched with water and the aqueous phase was extracted with dichloromethane (40 mL*2). The organic phase was dried, concentrated to dryness, and the residue was purified by column chromatography(mobile phase: ethyl acetate / petroleum ether 0 / 100 to 30 / 70) to give compound 6-d (127 mg, 41%). LC-MS (ESI): m / z = 330.7 (M+H)+. Synthesis of compound 6-c To a reaction vial charged with 6-d (120 mg, 0.363 mmol), dichloromethane (20 mL), ((2R,7aS)-2- fluorohexahydro-1H-pyrrolozin-7a-yl)methanol (87 mg, 0.544 mmol) was added sodium tert- butoxide (87 mg, 0.909 mmol) in an ice-water bath, and the reaction mixture was stirred for 3 hours, then was added ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methanol (87 mg, 0.544 mmol) and sodium tert-butanolate (87 mg, 0.909 mmol) and continued stirring for 2 hours. The reaction mixture was quenched with water and the aqueous phase was extracted with dichloromethane (40 mL*2). The organic phase was dried over anhydrous sodium sulfate, concentrated to dryness, and the residue was purified by column chromatography (mobile phase: ammonia methanol / dichloromethane 0 / 100 to 6 / 94) to give compound 6-c (80 mg, 49%). LC-MS (ESI): m / z = 453.6(M+H)+. Synthesis of compound 6-b A microwave tube charged with 6-c (120 mg, 0.265 mmol), ((2-fluoro-6-(methoxymethoxy)-8- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (204 mg, 0.397 mmol), tetrahydrofuran (12 mL), water (1.2 mL ), potassium phosphate (169 mg, 0.795 mmol) and cataCXium A Pd G3 (19 mg, 0.026 mmol) was degassed and purged with nitrogen for three times, then sealed and the reaction mixture was stirred at 65oC overnight. The next day, the reaction mixture was concentrated to dryness and the residue was purified by column chromatography (mobile phase: methanol / dichloromethane 0 / 100 to 6 / 94) to give compound 6-b (199 mg, 94%). LC-MS (ESI): m / z = 803.8 (M+H)+. Synthesis of compound 6-a A reaction flask charged with 6-b (199 mg, 0.248 mmol), DMF (10 mL) and cesium fluoride (376 mg, 2.478 mmol) with stirred for 1 h at room temperature under atmosphere of nitrogen. The reaction mixture was quenched with water and the aqueous phase was extracted with ethyl acetate (40 mL*2). The organic phase was washed with brine (30 mL*3), dried over anhydrous sodium sulfate, and concentrated to dryness to give compound 6-a (169 mg), which was used directly in the next step without purification. LC-MS (ESI): m / z =647.7 (M+H)+. Synthesis of compound 6 A reaction vial charged with 6-a (169 mg, 0.261 mmol), acetonitrile (20 mL), 1,4-dioxane / hydrochloride (4M , 2 mL, 8 mmol) was stirred at room temperature for 2 hours. The reaction mixture was concentrated to dryness, and the residue was added methanol (10 mL) and adjusted to pH 7 with saturated sodium bicarbonate solution. The mixture was concentrated to dryness and the residue was purified by column chromatography (mobile phase: methanol / dichloromethane 0 / 100 to 6 / 94) to give compound 6 (90 mg, 57%). LC-MS (ESI): m / z =603.7 (M+H)+;1H NMR (400M, CD3OD) δ: 10.18 (1H, d, J=10.0Hz), 7.90-7.80(1H, m), 7.38-7.27(2H, m), 7.22(1H, s), 5.34(1H, d, J=54.0Hz), 4.59(1H, d, J=14.4Hz), 4.39-4.21(2H, m), 3.68-3.57(1H, m), 3.54-3.31(3H, m), 3.13- 3.01(1H, m), 2.86-2.76(1H, m), 2.73(3H, s), 2.45-2.10(3H, m), 2.09-1.75(7H, m), 1.64-1.22(4H, m). Example 7 Synthetic route of compound 7

[0010] Synthesis of compound 7-g NaH (60%, 751 mg, 18.78 mmol) was added into a reaction flask charged with DMF (20 mL) under atmosphere of nitrogen in an ice-water bath. After stirred for 15 min, the above mixture was added a solution of 2-(tert-butyl)hydrazine-1,2-dicarboxylic acid-1-benzyl ester (2000 mg, 7.51 mmol) in DMF (5 mL) dropwise. After addition, the above mixture was warmed to room temperature and stirred for 1 hour, then cooled in an ice-water bath, and was added a solution of 2,2'-dichlorodiethyl ether (1149 mg, 8.04 mmol) in DMF (5 mL) dropwise. The reaction mixture was warmed to room temperature overnight. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with water, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by column chromatography (mobile phase: PE / EA 10 / 0 to 10 / 3) to give compound 7- g (1300 mg, 51%). LC-MS (ESI): m / z 237.1 (M-Boc+H)+. Synthesis of compound 7-f A reaction vial charged with 7-g (1300 mg, 3.86 mmol), DCM (10 mL) and trifluoroacetic acid (4467 mL, 39.18 mmol) was stirred at room temperature for 3 hours. The reaction mixture was concentrated and adjusted to basic by addition of ammonia in methanol (7 M), concentrated and the residue was purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to give compound 7-f (400 mg, 44%). LC-MS (ESI): m / z 237.2 (M+H)+. Synthesis of compound 7-e At room temperature, to a reaction vial were added 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (256 mg, 1.01 mmol), DCM (15 mL). After degassed and purged with nitrogen, the above mixture was cooled to -78°C in a dry ice-acetone bath, then was added DIPEA (274 mg, 2.12 mmol), 7-f (200 mg, 0.85 mmol). After addition, the reaction mixture was naturally warmed to room temperature and stirred overnight. The reaction mixture was added with water, and the aqueous phase was extracted with DCM. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by column chromatography (mobile phase: PE / EA 10 / 0 to 6 / 4) to give compound 7-e (300 mg, 78%). Synthesis of compound 7-d At room temperature, to a reaction vial were added 7-e (300 mg, 0.66 mmol), ((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methanol (137 mg, 0.86 mmol), 1,4-dioxane (10 mL) and DIPEA (214 mg, 1.65 mmol). After degassed and purged with nitrogen, the reaction mixture was stirred at 90°C overnight. The reaction mixture was concentrated and the residue was purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to give compound 7-d (240 mg, 63%). LC-MS (ESI): m / z 575.5 (M+H)+. Synthesis of compound 7-c At room temperature, to a microwave tube were added 7-d (130 mg, 0.23 mmol), ((2-fluoro-6- (methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1- yl)ethynyl)triisopropylsilane (139 mg, 0.27 mmol), cataCXium A Pd G3 (16 mg , 0.02 mmol), potassium phosphate (144 mg, 0.68 mmol), THF (2 mL) and water (0.5 mL). The mixture was degassed and purged with nitrogen, sealed, and stirred at 65 °C overnight. The reaction mixture was concentrated and the residue was purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to give compound 7-c (150 mg, 72%). LC-MS (ESI): m / z 925.4 (M+H)+. Synthesis of compound 7-b At room temperature, to a reaction flask were added 7-c (130 mg, 0.14 mmol) and acetonitrile (5 mL). After degassed and purged with nitrogen, and cooled to 0 °C, the above mixture was added HCl / 1,4-dioxane (4.0 M, 1 mL). The reaction mixture was stirred at 0°C for 3 hours, concentrated at low temperature to give the crude compound 7-b (150 mg). LC-MS (ESI): m / z 881.4 (M+H)+. Synthesis of compound 7-a At room temperature, to a reaction vial were added crude compound 7-b (150 mg, 0.14 mmol), methanol (14 mL) and Pd / C 10% (120 mg). The reaction mixture was degassed and purged with H2and stirred at room temperature overnight. The reaction mixture was filtered and the filtrate was concentrated to give the crude compound 7-a (105 mg). LC-MS (ESI): m / z 747.4 (M+H)+. Synthesis of compound 7 At room temperature, to a reaction flask were added crude compound 7-a (105 mg, 0.14 mmol), DMF (3 mL) and cesium fluoride (107 mg, 0.70 mmol). After degassed and purged with nitrogen, the reaction mixture was stirred at 60°C for 5 hours. The reaction mixture was filtered and the filtrate was purified by prep-HPLC to give compound 7 (12 mg, 14%). LC-MS (ESI): m / z 591.6 (M+H)+. Example 8 Synthetic route of compound 8 Synthesis of compound 8-b At room temperature, to a microwave tube were added 7-d (100 mg, 0.17 mmol), 2-(8-ethyl-7- fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (75 mg, 0.21 mmol), cataCXium A Pd G3 (13 mg, 0.02 mmol), potassium phosphate (111 mg, 0.52 mmol), THF (2 mL) and water (0.5 mL). The mixture was degassed and purged with nitrogen, sealed, and stirred at 65 °C overnight. The reaction mixture was concentrated and the residue was purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to give compound 8-b (110 mg, 82%). LC-MS (ESI): m / z 773.8 (M+H)+. Synthesis of compound 8-a At room temperature, to a reaction vial were added 8-b (110 mg, 0.14 mmol) and acetonitrile (5 mL). After degassed and purged with nitrogen, the above mixture was cooled down to 0 °C, the mixture was added HCl / 1,4-dioxane (4.0 M, 1 mL), then stirred at 0°C for 3 hours. The reaction mixture was concentrated at low temperature to give the crude compound 8-a (104 mg). LC-MS (ESI): m / z 729.7 (M+H)+. Synthesis of compound 8 At room temperature, to a reaction vial were added crude 8-a (104 mg, 0.14 mmol), methanol (10 mL) and Pd / C 10% (100 mg). After degassed and purged with H2, the reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered, and the filtrate was concentrated and the residue was purified by prep-HPLC to give compound 8 (18 mg, 21%). LC-MS (ESI): m / z 595.7 (M+H)+;1H NMR (400MHz, DMSO-d6): δ 10.31 (1H, s), 9.97 (1H, s), 7.82-7.70 (1H, dd, J =9.2,6.4 Hz), 7.42-7.27 (2H, m), 7.06-6.99 (1H, d, J =2.0 Hz), 6.25-6.15 (1H, t, J =6.0 Hz), 5.40-5.16(1H, d, J=53.6Hz), 4.43-3.89 (6H, m),3.86-3.68 (2H, t, J =4.4 Hz), 3.23-2.94 (5H, m), 2.89-2.76 (1H, m), 2.43-2.24 (1H, m), 2.23-1.64 (7H, m), 0.72 (3H, t, J =7.2 Hz).. Example 9 Synthetic route of compound 9 Synthesis of compound 9-f Potassium tert-butoxide (2243 mg, 20.00 mmol), THF (40 mL) were added to a reaction flask at room temperature. After degassed and purged with nitrogen, the above mixture was added N-Boc hydroxylamine (1331 mg, 10.00 mmol) batchwise, and stirred for 1 hour at room temperature after addition, then was added a solution of 1,5-dibromopentane (2299 mg, 10.00 mmol) in THF (10 mL) dropwise. After dropwise addition, the reaction mixture was stirred at 75°C overnight. The reaction mixture was added 100 mL of water and 100 mL of ethyl acetate. The mixture was partitioned and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with water, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by column chromatography (mobile phase: PE / EA 10 / 0 to 10 / 1) to give compound 9-f (900 mg, 45%). LC-MS (ESI): m / z 146.2 (M-t-Bu+H)+. Synthesis of compound 9-e Compound 9-f (200 mg, 0.99 mmol) and acetonitrile (5 mL) were added in a reaction flask at room temperature. After degassed and purged with nitrogen, the above mixture was cooled down to 0 °C, the mixture was added HCl / 1,4-dioxane (4.0 M, 1 mL), then stirred at 0°C for 3 hours. The reaction mixture was concentrated at low temperature and water and ethyl acetate were added. The liquid was partitioned and the aqueous phase was lyophilized to give compound 9-e (65 mg, 48%). LC- MS (ESI): m / z 102.2 (M-HCl+H)+. Synthesis of compound 9-d 2,4,7-Trichloro-8-fluoropyrido[4,3-d]pyrimidine (143 mg, 0.57 mmol) and DCM (10 mL) were added to a reaction vial at room temperature. After degassed and purged with nitrogen, the above mixture was cooled to -78°C in a dry ice-acetone bath and was added DIPEA (183 mg, 1.42 mmol) and 9-e (65 mg, 0.47 mmol). After addition, the reaction mixture was naturally warmed to room temperature and stirred overnight. The reaction mixture was added with water, and the aqueous phase was extracted with DCM. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by column chromatography (mobile phase: PE / EA 10 / 0 to 6 / 4) to give compound 9-d (90 mg, 60%). LC-MS (ESI): m / z 317.5 (M+H)+. Synthesis of compound 9-c At room temperature, to a reaction vial were added 9-d (90 mg, 0.28 mmol), ((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methanol (68 mg, 0.43 mmol), 1,4-dioxane (5 mL) and DIPEA (110 mg, 0.85 mmol). After degassed and purged with nitrogen, the reaction mixture was stirred at 90°C overnight, then was concentrated and the residue was purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to give compound 9-c (80 mg, 64%). Synthesis of compound 9-b At room temperature, to a microwave tube were added 9-c (50 mg, 0.11 mmol), ((2-fluoro-6- (methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1- yl)ethynyl)triisopropylsilane (70 mg, 0.14 mmol), cataCXium A Pd G3 (8 mg. 0.01 mmol), potassium phosphate (72 mg, 0.34 mmol), THF (2 mL), and water (0.5 mL). The mixture was degassed and purged with nitrogen, sealed, and stirred at 65 °C overnight. The reaction mixture was concentrated and the residue was purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to give compound 9-b (55 mg, 61%). LC-MS (ESI): m / z 790.8 (M+H)+. Synthesis of compound 9-a At room temperature, to a reaction vial were added 9-b (55 mg, 0.07 mmol) and acetonitrile (5 mL). After degassed and purged with nitrogen, the above mixture was cooled down to 0 °C, was added HCl / 1,4-dioxane (4.0 M, 1 mL). It was stirred at 0°C for 3 hours. The reaction mixture was concentrated at low temperature to give the crude compound 9-a (60 mg). LC-MS (ESI): m / z 746.8 (M+H)+. Synthesis of compound 9 At room temperature, to a reaction flask were added crude compound 9-a (60 mg, 0.07 mmol), DMF (3 mL), cesium fluoride (106 mg, 0.70 mmol). After degassed and purged with nitrogen, the reaction mixture was stirred at 60°C for 3 hours. The reaction mixture was filtered and the filtrate was purified by prep-HPLC to give compound 9 (8 mg, 19%). LC-MS (ESI): m / z 590.2 (M+H)+. Example 10 Synthetic route of compound 10 Synthesis of compound 10-a At room temperature, to a microwave tube were added 9-c (15 mg, 0.03 mmol), 2-(8-ethyl-7-fluoro- 3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (15 mg, 0.04 mmol), cataCXium A Pd G3 (3 mg, 0.01 mmol), phosphate potassium (22 mg, 0.10 mmol), THF (2 mL), and water (0.5 mL). The mixture was degassed and purged with nitrogen, sealed, and stirred at 65 °C overnight. The reaction mixture was concentrated and the residue was purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to give compound 10-a (15 mg, 69%). LC-MS (ESI): m / z 638.8 (M+H)+. Synthesis of compound 10 At room temperature, to a reaction flask were added 10-a (15 mg, 0.02 mmol) and acetonitrile (2 mL). After degassed and purged with nitrogen, the above mixture was cooled down to 0 °C, the mixture was added HCl / 1,4-dioxane (4.0 M, 0.3 mL). The reaction mixture was stirred at 0°C for 3 hours. The reaction mixture was concentrated and the residue was purified by prep-HPLC to give compound 10 (1.3 mg, 9%). LC-MS (ESI): m / z 594.7 (M+H)+. Example 11 Synthetic route of compound 11 Synthesis of compound 11-b To a 30 mL microwave tube were added 3-b (50 mg, 0.093 mmol), ((2-fluoro-8-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (46 mg, 0.10 mmol), methanesulfonic acid [butylbis(1-adamantyl)phosphine] (2-amino-1,1' -biphenyl-2- yl)palladium(II) (7 mg, 0.009 mmol), potassium phosphate (59 mg, 0.28 mmol), tetrahydrofuran (6 mL) and water (1.5 mL). After degassed and purged with nitrogen several times, the microwave tube was sealed. The reaction mixture was stirred at 65 °C and stirred overnight. To the reaction mixture, water was added and the aqueous phase was extracted with ethyl acetate (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness and the crude was purified by flash column chromatography (mobile phase: dichloromethane: methanol = 10:1 / dichloromethane, 0-30%) to give compound 11-b (61 mg, 79%). Synthesis of compound 11-a To a solution of 11-b (61 mg, 0.074 mmol) in DMF (8 mL) was added cesium fluoride (112 mg, 0.74 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight. Water was added and the aqueous phase was extracted with ethyl acetate (50 mL). The organic phase was washed twice with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to give compound 11-a (49 mg, 99%). LC-MS (ESI): m / z 673.8 (M+H)+. Synthesis of compound 11 To a solution of 11-a (49 mg, 0.073 mmol) in acetonitrile (8 mL) was added a HCl / 1,4-dioxane (4 M, 1 mL) at room temperature. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated to dryness and the crude was purified by prep-HPLC to give compound 11 (7.5 mg, 18%). LC-MS (ESI): m / z 573.3 (M+H)+. Example 12 Synthetic route of compound 12 Synthesis of compound 12-a To a 10 mL microwave tube were added 3-b (50 mg, 0.093 mmol), ((6-fluoro-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylmethylsilyl)ethynyl)naphthalen-2- yl)oxy)triisopropylsilane (64 mg, 0.10 mmol), methanesulfonated [butylbis(1-adamantyl) alkyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (7 mg, 0.009 mmol), potassium phosphate (59 mg, 0.28 mmol), tetrahydrofuran (2.5 mL) and water (0.5 mL). After degassed and purged with nitrogen several times, the microwave tube was sealed. The reaction mixture was stirred at 65 °C overnight. To the reaction mixture, water was added, the aqueous phase was extracted with ethyl acetate (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness and the crude product was purified by flash column chromatography (mobile phase: methanol / dichloromethane, 0-100%) to obtain 12-a (89 mg, 96%). Synthesis of compound 12 To a solution of 12-a (89 mg, 0.089 mmol) in DMF (8 mL) was added cesium fluoride (68 mg, 0.45 mmol) at room temperature, and the reaction mixture was stirred at room temperature overnight. Water was added to the reaction mixture and the aqueous phase was extracted with ethyl acetate (30 mL). The organic phase was washed twice with brine, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated to dryness, and the crude was purified by prep-HPLC to give compound 12 (35 mg, 57%). LC-MS (ESI): m / z 689.3 (M+H)+;1H NMR (400 MHz, CDCl3): δ 9.20–9.10 (1H, m), 7.64–7.55 (1H, m), 7.27–7.10 (3H, m), 5.30 (1H, d, J = 54.0 Hz), 4.37–4.14 (4H, m), 3.99–3.83 (1H, m), 3.35–3.10 (4H, m), 3.04–2.95 (1H, m), 2.87–2.74 (1H, m), 2.36–1.58 (13H, m), 1.61–1.41 (9H, m). Example 13 Synthetic route of compound 13 and 14

[0011] Synthesis of compound 13-c To a solution of 3-c (150 mg, 0.36 mmol) in dichloromethane (15 mL) was added {1- [(dimethylamino)methyl]cyclopropyl}methanol (70 mg, 0.54 mmol), followed by slow addition of sodium tert-butoxide (69 mg, 0.72 mmol) in an ice-water bath. The temperature was slowly warmed to room temperature and the reaction mixture was stirred at room temperature overnight. Water was added to the reaction mixture and the aqueous phase was extracted with dichloromethane (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated to dryness. The crude was purified by flash column chromatography (mobile phase: DCM: MeOH=10:1 / DCM, 0-50%) to give compound 13-c (140 mg, 76%). LC-MS (ESI): m / z 509.5 (M+H)+. Synthesis of compound 13-b To a 10 mL microwave tube were added 13-c (140 mg, 0.28 mmol), ((2-fluoro-6- (methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1- yl)ethynyl)triisopropylsilane (169 mg, 0.33 mmol), methanesulfonic acid [n-butylbis(1- adamantyl )phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II)cataCXium A Pd G3 (20 mg, 0.028 mmol), potassium phosphate (175 mg, 0.83 mmol), tetrahydrofuran (2.5 mL) and water (0.5 mL). After degassed and purged with nitrogen several times, the microwave the tube was sealed. The reaction mixture was stirred at 65°C overnight. The reaction mixture was concentrated to dryness and the crude was purified by flash column chromatography (mobile phase: DCM: MeOH=10:1 / DCM, 0-100%) to give compound 13-b (230 mg, 97%). LC-MS (ESI): m / z 860.2 (M+H)+. Synthesis of compound 13-a To a solution of 13-b (230 mg, 0.27 mmol) in DMF (6 mL) was added cesium fluoride (203 mg, 1.34 mmol) and the reaction mixture was stirred at room temperature overnight. Water was added to the reaction mixture and the aqueous phase was extracted with ethyl acetate (50 mL). The organic phase was washed twice with brine, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated to dryness to give compound 13-a (172 mg, 91%). LC-MS (ESI): m / z 703.9 (M+H)+. Synthesis of compounds 13 and 14 To a solution of 13-a (100 mg, 0.14 mmol) in acetonitrile (15 mL) was added a HCl / 1,4-dioxane (4 M, 2.5 mL) in an ice-water bath. The reaction mixture was stirred at this temperature for 1 hour. The reaction mixture was warmed to room temperature and stirred for another 3 hours. It was neutralized by addition of saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness and the crude was purified by prep-HPLC to give compound 13 (19 mg, 24%) and 14 (12.2 mg, 13%). Compound 13：LC-MS (ESI): m / z 559.3 (M+H)+;1H NMR (400 MHz, CDCl3): δ 10.15 (1H, s), 7.54 (1H, dd, J = 9.6, 5.6 Hz), 7.24 (1H, s), 7.09 (1H, t, J = 8.8 Hz), 7.02(1H, s), 4.61 – 4.50 (1H, m), 4.50 – 4.41 (1H, d, J = 10.8 Hz), 4.18 (1H, d, J = 10.4 Hz), 4.08 – 3.92 (2H, m), 3.19 – 3.02 (2H, m), 2.77 (1H, s), 2.74 – 2.65 (1H, m), 2.39 (6H, s), 1.97 – 1.91 (3H, m), 1.76 – 1.66 (5H, m), 0.73 (2H, s), 0.56 (2H, dd, J = 16.0, 9.6 Hz)；compound 14：LC-MS (ESI): m / z 659.3 (M+H)+. Example 14 Synthetic route of compound 15 Synthesis of compound 15-f Sodium hydride (60%, 0.75 g, 18.78 mmol) was added in batches to a solution of 2-(tert- butyl)hydrazine-1,2-dicarboxylic acid-1-benzyl ester (2 g, 7.51 mmol) in DMF (60 mL) in an ice- water bath. The mixture was stirred for 30 min at the same temperature, then at room temperature for 1 h, and then cooled down to 0 °C in an ice-water bath, and slowly added 1,6 -Dichlorohexane (1.16 g, 7.51 mmol). After addition, the mixture was slowly warmed to room temperature and stirred overnight. Saturated aqueous ammonium chloride was added to the reaction mixture and the aqueous phase was extracted with ethyl acetate (30 mL*2), the combined organic phases were washed twice with water and twice with brine. The organic phases were dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and the crude product was purified by flash column chromatography (mobile phase: ethyl acetate / petroleum ether, 0-10%) to obtain 15-f (0.86 g, 33%). LC-MS (ESI): m / z 249.3 (M-100+H)+. Synthesis of compound 15-e To a solution of 15-f (860 mg, 2.47 mmol) in ethyl acetate (25 mL) was added Pd / C (10%, 200 mg, 1.88 mmol) at room temperature, and the reaction mixture was degassed and purged with a hydrogen balloon several times, then was stirred at room temperature overnight. The reaction mixture was filtered to remove the Pd / C and the filtrate was concentrated to dryness to give compound 15-e (530 mg, 100.00%). LC-MS (ESI): m / z 159.2 (M-56+H)+. Synthesis of compound 15-d To a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (100 mg, 0.396 mmol) in dichloromethane (20 mL) was added 15-e (93 mg, 0.44 mmol) and N,N-diisopropylethylamine (154 mg, 1.19 mmol) in an acetone-dry ice-water bath and the mixture was stirred for 2 h at this temperature. Water was added to the reaction mixture and the aqueous phase was extracted with dichloromethane (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness and the crude was purified by flash column chromatography (mobile phase: ethyl acetate / petroleum ether, 0-10%) to give compound 15-d (169 mg, 99%). LC- MS (ESI): m / z 430.4 (M+H)+. Synthesis of compound 15-c To a solution of 15-d (169 mg, 0.39 mmol) in dichloromethane (15 mL) was added ((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methanol (188 mg, 1.18 mmol) in an ice-water bath, followed by slow addition of sodium tert-butoxide (151 mg, 1.57 mmol), and the mixture was stirred at this temperature for 5 hours. Then water was added and the aqueous phase was extracted with dichloromethane (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness and the crude was purified by flash column chromatography (mobile phase: dichloromethane: methanol=10:1 / dichloromethane, 0-50%) to give compound 15-c (154 mg, 70%). LC-MS (ESI): m / z 553.6 (M+H)+. Synthesis of compound 15-b To a 10 mL of microwave tube were added 15-c (154 mg, 0.28 mmol), ((6-fluoro-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylmethylsilyl)ethynyl)naphthalen-2- yl)oxy)triisopropylsilane (209 mg, 0.334 mmol), methanesulfonic acid [n-butylbis(1 - adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (20 mg, 0.028 mmol), potassium phosphate (177 mg, 0.84 mmol), tetrahydrofuran (2.5 mL) and water (0.5 mL). After degassed and purged with nitrogen several times, the microwave tube was sealed. The reaction mixture was stirred at 65°C overnight. The reaction mixture was added water, and the aqueous phase was extracted with ethyl acetate (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain 15-b (280 mg, 99%). The crude product was used directly in the next step without purification. Synthesis of compound 15-a Cesium fluoride (209 mg, 1.38 mmol) was added to a solution of 15-b (280 mg, 0.28 mmol) in DMF (8 mL) at room temperature, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was added water, and the aqueous phase was extracted with ethyl acetate (30 mL). The organic phase was washed twice with brine, dried over anhydrous sodium sulfate, filtered. The organic phase was concentrated to dryness, and the crude was purified by flash column chromatography (mobile phase: dichloromethane: methanol = 10:1 / dichloromethane, 0-50%) to obtain 15-a (166 mg, 86%). LC-MS (ESI): m / z 703.8 (M+H)+. Synthesis of compound 15 To a solution of 15-a (166 mg, 0.24 mmol) in acetonitrile (10 mL) was added HCl / 1,4-dioxane (4M, 1.5 mL) at room temperature. The reaction mixture was stirred at room temperature overnight. It was neutralized by addition of saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness and the crude was purified by prep-HPLC to give compound 15 (69 mg, 49%). LC-MS (ESI): m / z 603.3 (M+H)+;1H NMR (400 MHz, CDCl3): δ 10.14 (1H, d, J = 35.6 Hz), 7.54-7.38 (1H, m), 7.25 (1H, d, J = 46.4,Hz), 7.14-7.00 (2H, m), 5.29 (1H, dd, J = 53.6, 13.2 Hz), 4.62 (1H, s), 4.25 – 4.11 (2H, m), 4.10 – 3.77 (2H, m), 3.34 – 3.06 (5H, m), 3.02 – 2.93 (1H, m), 2.75 (1H, s), 2.43 – 2.04 (5H, m), 2.02 – 1.86 (4H, m), 1.73 – 1.40(6H, m). Example 15 Synthetic route of compound 16 and 17 Synthesis of compound 16-d A reaction vial charged with tert-butyl tetrahydropyridazine-1(2H)-carboxylate (148 mg, 0.792 mmol), dichloromethane (30 mL), diisopropylethylamine (0.393 mL, 2.377 mmol), and 2,4,7- trichloro-8-fluoropyrido[4,3-d]pyrimidine (200 mg, 0.792 mmol) was cooled in a dry ice-acetone bath. The reaction mixture was stirred under protection of nitrogen for 1 hour. The reaction mixture was quenched with water and the aqueous phase was extracted with dichloromethane (50 mL*2). The organic phase was dried, concentrated to dryness and the residue was purified by column chromatography (mobile phase: ethyl acetate / petroleum ether 0 / 100 to 10 / 90) to afford compound 16-d (270 mg, 85%). LC-MS (ESI): m / z = 402.1 (M+H)+. Synthesis of compound 16-c A reaction vial charged with 16-d (100 mg, 0.249 mmol), dichloromethane (30 mL), ((2R,7aS)-2- fluorohexahydro-1H-pyrrolozin-7a-yl)methanol (47 mg, 0.298 mmol) was added sodium tert- butoxide (60 mg, 0.622 mmol) in an ice-water bath. After addition, the reaction mixture was stirred in an ice-water bath for half an hour, supplemented with sodium tert-butanol (60 mg, 0.622 mmol), and continued stirring for half an hour; then supplemented with sodium tert-butanol (60 mg, 0.622 mmol), and continued stirring for half an hour; and supplemented again with sodium tert-butanol (60 mg, 0.622 mmol), and continued stirring for half an hour. The reaction mixture was quenched with water and the aqueous phase was extracted with dichloromethane (50 mL*2). The organic phase was dried over anhydrous sodium sulfate, concentrated to dryness, and the residue was purified by column chromatography (mobile phase: ammonia methanol / dichloromethane 0 / 100 to 6 / 94) to give compound 16-c (114 mg, 87%). LC-MS (ESI): m / z = 525.8(M+H)+. Synthesis of compound 16-b To a microwave tube were added 16-c (114 mg, 0.217 mmol), ((2-fluoro-6-(methoxymethoxy)-8- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (167 mg, 0.326 mmol), tetrahydrofuran (15 mL), water (1.5 mL), potassium phosphate (138 mg, 0.651 mmol), cataCXium A Pd G3 (16 mg, 0.022 mmol). After degassed and purged with nitrogen for three times, the microwave tube was sealed, and the reaction mixture was stirred at 65oC overnight.The next day, the reaction mixture was concentrated to dryness and the residue was purified by column chromatography (mobile phase: methanol / dichloromethane 0 / 100 to 2 / 98) to give compound 16-b (198 mg, 100%). LC-MS (ESI): m / z = 875.7 (M+H)+. Synthesis of compound 16-a To a reaction flask were added 16-b (198 mg, 0.226 mmol), DMF (10 mL), cesium fluoride (343 mg, 2.26 mmol), and the reaction mixture was stirred for 1 h at room temperature under atmosphere of nitrogen. The reaction mixture was quenched with water and the aqueous phase was extracted with ethyl acetate (50 mL*2). The organic phase was washed with brine (50 mL*3), dried over anhydrous sodium sulfate, concentrated to dryness, and the residue was purified by column chromatography (mobile phase: methanol / dichloromethane 0 / 100 to 5 / 95) to give compound 16-a (127 mg, 78%). LC-MS (ESI): m / z =719.9 (M+H)+. Synthesis of compounds 16 and 17 A reaction vial charged with 16-a (127 mg, 0.177 mmol) and formic acid (10 mL) was stirred at room temperature for 10 hours. The reaction mixture was concentrated to dryness, purified by prep- HPLC (ammonium bicarbonate) and lyophilized to give compounds 16 (25 mg, 25%) and 17 (5 mg, 4%). Compound 16, LC-MS (ESI): m / z =575.2 (M+H)+;1H NMR (400M, DMSO-d6) δ 10.29(1H, s), 10.14(1H, s), 8.00-7.92(1H, m), 7.46(1H, t, J=8.8Hz), 7.38(1H, d, J=2.4Hz), 7.16(1H, d, J=2.0Hz), 5.63(1H, t, J=6.4Hz), 5.28(1H, d, J=53.6Hz), 4.29-3.95(4H, m), 3.92(1H, s), 3.15- 2.96(5H, m), 2.88-2.76(1H, m), 2.16-1.65(10H, m). Compound 17, LC-MS (ESI): m / z =675.3 (M+H)+. Example 16 Synthetic route of compound 18

[0012] Synthesis of compound 18-d A reaction vial charged with tert-butyl pyrazolidine-1-carboxylate (136 mg, 0.79 mmol), dichloromethane (30 mL), diisopropylethylamine (0.393 mL, 2.38 mmol) was cooled in a dry ice- acetone bath and added 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (200 mg, 0.79 mmol) . The reaction mixture was stirred under protection of nitrogen for 1 hour, then was quenched with water and the aqueous phase was extracted with dichloromethane (50 mL*2). The organic phase was dried and concentrated to dryness to give compound 18-d (307 mg, 100%), which was used without purification in the next step. LC-MS (ESI): m / z = 388.1 (M+H)+. Synthesis of compound 18-c A reaction vial charged with 18-d (307 mg, 0.79 mmol), dichloromethane (30 mL), ((2R,7aS)-2- fluorohexahydro-1H-pyrrolozin-7a-yl)methanol (126 mg, 0.79 mmol) was added sodium tert- butoxide (190 mg, 1.977 mmol) in an ice-water bath, and the reaction mixture was stirred for 1 hour. Supplemented with sodium tert-butanol (190 mg, 1.977 mmol) and continued stirring for 1 hour. The reaction mixture was quenched with water and the aqueous phase was extracted with dichloromethane (80 mL*2). The organic phase was dried over anhydrous sodium sulfate, concentrated to dryness, and the residue was purified by column chromatography (mobile phase: methanol / dichloromethane 0 / 100 to 3 / 97) to give compound 18-c (217 mg, 54%). LC-MS (ESI): m / z = 511.5(M+H)+. Synthesis of compound 18-b To a microwave tube were added 18-c (217 mg, 0.42 mmol), ((2-fluoro-6-(methoxymethoxy)-8- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (326 mg, 0.637 mmol), tetrahydrofuran (15 mL), water (1.5 mL ), potassium phosphate (270 mg, 1.274 mmol), cataCXium A Pd G3 (31 mg, 0.042 mmol). After degassed and purged with nitrogen for three times, the microwave tube was sealed and stirred at 65oC overnight.The next day, the reaction mixture was concentrated to dryness and the residue was purified by column chromatography (mobile phase: methanol / dichloromethane 0 / 100 to 4 / 96) to give compound 18-b (396 mg, 100%). LC-MS (ESI): m / z = 861.7 (M+H)+. Synthesis of compound 18-a To a reaction flask were added 18-b (396 mg, 0.46 mmol), DMF (10 mL), cesium fluoride (699 mg, 4.599 mmol) and the reaction mixture stirred for 1 h at room temperature under protection of nitrogen, then was quenched with water and the aqueous phase was extracted with ethyl acetate (50 mL*2). The organic phase was washed with brine (50 mL*3), dried over anhydrous sodium sulfate, concentrated to dryness, and the residue was purified by column chromatography (mobile phase: methanol / dichloromethane 0 / 100 to 5 / 95) to give compound 18-a (236 mg, 73%). LC-MS (ESI): m / z =705 (M+H)+. Synthesis of compound 18 A reaction vial charged with 18-a (100 mg, 0.14 mmol) and formic acid (10 mL) was stirred at room temperature overnight. The following day, the reaction mixture was concentrated to dryness, purified by prep-HPLC (ammonium bicarbonate) and lyophilized to give compound 18 (19 mg, 24%). LC-MS (ESI): m / z =561.3 (M+H)+;1H NMR (400M, DMSO-d6): δ 10.19(1H, d, J=9.2Hz), 10.04(1H, d, J=44.8Hz), 8.03-7.92(1H, m), 7.76-6.05(1H, m), 7.46(1H, t, J=8.8Hz), 7.41-7.35(1H, m), 7.20-7.10(1H, m), 5.28(1H, d, J=55.2Hz), 4.23-3.96(3H, m), 3.92(1H, d, J=8.0Hz), 3.83(1H, t, J=7.2Hz), 3.23-2.98(5H, m), 2.88-2.78(1H, m), 2.21-1.70(8H, m). Example 17 Synthetic route of compound 19 Synthesis of compound 19 A reaction vial charged with compound 4 (40 mg, 0.068 mmol), methylene chloride (15 mL) and diisopropylethylamine (56 uL, 0.34 mmol) was added methylamine carbonyl chloride (14 mg, 0.134 mmol) in an ice-water bath. After addition, the reaction mixture was stirred at room temperature overnight. The next day, the reaction mixture was quenched with saturated sodium bicarbonate solution, extracted with dichloromethane (50 mL*2), dried over anhydrous sodium sulfate, concentrated to dryness, purified by prep-HPLC (trifluoroacetic acid), lyophilized to give compound 19 (26 mg, 59%). LC-MS (ESI): m / z =646.3 (M+H)+. Example 18 Synthetic route of compound 20 Synthesis of compound 20-d To a reaction flask were added 3-b (290 mg, 0.54 mmol), acetonitrile (20 mL), hydrochloride / 1,4- dioxane (4 M, 2 mL), and the reaction mixture was stirred at room temperature overnight under protection of nitrogen. The next day, the reaction mixture was concentrated to dryness, and the residue was added 20 mL of methanol, adjusted to pH 7 with saturated sodium bicarbonate solution. The sovents were removed, and the residue was redissolved in dichloromethane, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to give compound 20-d (288 mg, 100%), which was used directly in the next step without purification. LC-MS (ESI): m / z = 439.6 (M+H)+. Synthesis of compound 20-c To a microwave tube were added 20-d (280 mg, 0.64 mmol), ((2-fluoro-6-(methoxymethoxy)-8- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (490 mg, 0.957 mmol), tetrahydrofuran (12 mL), water (1.2 mL ), potassium phosphate (406 mg, 1.914 mmol), cataCXium A Pd G3 (93 mg, 0.128 mmol). After degassed and purged with nitrogen for three times, the microwave tube was sealed and stirred at 65oC overnight.The next day, the reaction mixture was concentrated to dryness and the residue was purified by column chromatography (mobile phase: methanol / dichloromethane 0 / 100 to 10 / 90) to give compound 20-c (380 mg, 75%). LC-MS (ESI): m / z = 789.9 (M+H)+. Synthesis of compound 20-b To a reaction flask were added 20-c (380 mg, 0.48 mmol), DMF (10 mL), cesium fluoride (732 mg, 4.816 mmol) and the reaction mixture was stirred for 1 h at room temperature under protection of nitrogen. The reaction mixture was quenched with water and the aqueous phase was extracted with ethyl acetate (50 mL*2). The organic phase was washed with brine (50 mL*3), dried over anhydrous sodium sulfate and concentrated to dryness to give compound 20-b (323 mg, 100%), which was used directly in the next step without purification. LC-MS (ESI): m / z =633.8 (M+H)+. Synthesis of compound 20-a A reaction vial charged with 20-b (50 mg, 0.079 mmol), dichloromethane (20 mL) and DIPEA (0.131 mL, 0.79 mmol) was added ethyl chloroformate (75 uL, 0.79 mmol) dropwise with stirring at room temperature and stirred for half an hour at room temperature under protection of nitrogen. The reaction mixture was quenched with saturated sodium bicarbonate solution and the aqueous phase was extracted with dichloromethane (50 mL*2). The organic phase was concentrated to dryness and the residue was purified by column chromatography (mobile phase: ethyl acetate / petroleum ether 0 / 100 to 50 / 50) to give compound 20-a (50 mg, 90%). LC-MS (ESI): m / z =705.4 (M+H)+. Synthesis of compound 20 A reaction vial charged with 20-a (50 mg, 0.071 mmol), acetonitrile (10 mL) and hydrochloride / 1,4- dioxane (4M, 1 mL, 4 mmol) was stirred at room temperature for 2 hours. The reaction mixture was concentrated to dryness at room temperature, and the residue was added methanol (20 mL) and adjusted to pH 7 with saturated sodium bicarbonate solution. The mixture was concentrated to dryness, purified by column chromatography (mobile phase: methanol / dichloromethane 0 / 100 to 6 / 94), purified by prep-HPLC (ammonium bicarbonate) and lyophilized to give compound 20 (6 mg, 13%). LC-MS (ESI): m / z =661.3 (M+H)+. Example 19 Synthetic route of compound 21

[0013] Synthesis of compound 21-e Difluoromethyl (2-pyridyl) sulfone (4118 mg, 21.32 mmol) and DMF (50 mL) were added to a reaction flask at room temperature. After degassed and purged with nitrogen, the above mixture was cooled down to -50 °C, was added a solution of ethyl 2,5-dioxohexahydro-1H-pyrrolizine-7a- carboxylate (5000 mg, 23.67 mmol) in DMF (50 mL) dropwise while the temperature was controlled to be no higher than -45°C. After addition, the reaction mixture was naturally warmed to room temperature for 1 hour. The reaction mixture was added saturated aqueous ammonium chloride solution (30 mL) to quench the reaction, then was added concentrated hydrochloric acid (37% wt, 18 mL) and stirred at room temperature for 1 hour. The resulting mixture was added water, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography (mobile phase: PE / DCM 10 / 0 to 0 / 10) to give compound 21-e (1000 mg, 19%). LC-MS (ESI): m / z 246.2 (M+H)+. Synthesis of compound 21-d A solution of lithium aluminum hydride (1M, 6.52 mL) in tetrahydrofuran was added to a reaction flask at room temperature. After degassed and purged with nitrogen, the above mixture was cooled down to 0°C, was added a solution of 21-e (800 mg, 3.26 mmol) in THF (5 mL) dropwise. After addition, the reaction mixture was stirred at 65°C for 3 hours. The reaction mixture was cooled to room temperature and quenched by the addition of methanol (30 mL) under protection of nitrogen, then about 3 g of sodium sulfate decahydrate was added and the mixture was stirred at room temperature for 2 hours. The mixture was filtered and the filter cake was washed with methanol. The filtrates were combined, concentrated and the residue was purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to give compound 21-d (130 mg, 23%). LC-MS (ESI): m / z 172.2 (M+H)+. Synthesis of compound 21-c 3-c (379 mg, 0.91 mmol), 21-d (130 mg, 0.76 mmol), 1,4-dioxane (10 mL) and DIPEA (294 mg, 2.27 mmol) were added to a reaction vial at room temperature. After degassed and purged with nitrogen, the reaction mixture was stirred at 90°C overnight. The reaction mixture was concentrated and the residue was purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to give compound 21-c (140 mg, 33%). LC-MS (ESI): m / z 551.8 (M+H)+. Synthesis of compound 21-b At room temperature, 21-c (140 mg, 0.25 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (156 mg, 0.30 mmol), cataCXium A Pd G3 ( 19 mg, 0.03 mmol), potassium phosphate (162 mg, 0.76 mmol), THF (2 mL) and water (0.5 mL) were comnined in a microwave tube. The mixture was degassed and purged with nitrogen, sealed, and stirred at 65°C overnight. The reaction mixture was concentrated and the residue was purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to give compound 21-b (90 mg, 39%). LC-MS (ESI): m / z 902.0 (M+H)+. Synthesis of compound 21-a At room temperature, 21-b (90 mg, 0.10 mmol) and acetonitrile (5 mL) were added to a reaction flask. After degassed and purged with nitrogen, the above mixture was cooled down to 0 °C, the above mixture was added HCl / 1,4-dioxane (4.0 M, 1 mL). The reaction mixture was stirred at 0°C for 3 hours. The reaction mixture was concentrated at low temperature to give the crude compound 21-a (130 mg). LC-MS (ESI): m / z 757.5 (M+H)+. Synthesis of compound 21 To a reaction flask, crude compound 21-a (130 mg, about 0.10 mmol), DMF (3 mL) and cesium fluoride (76 mg, 0.50 mmol) were added at room temperature. After degassed and purged with nitrogen, the reaction mixture was stirred at 60°C for 1 hour. The reaction mixture was filtered and the filtrate was purified by prep-HPLC to give compound 21 (4 mg, 7%). LC-MS (ESI): m / z 601.6 (M+H)+. Example 20 Synthetic route of compound 22 Synthesis of compound 22-c At room temperature, 3-c (200 mg, 0.48 mmol), (2-(difluoromethylene)tetrahydro-1H-pyrrolizin- 7A(5H)-yl)methanol (118 mg, 0.62 mmol), 1,4-dioxane (10 mL) and DIPEA (186 mg, 1.44 mmol) were added to a reaction vial. After degassed and purged with nitrogen, the reaction mixture was stirred at 90°C overnight. The reaction mixture was concentrated and the residue was purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to give compound 22-c (140 mg, 51%). LC-MS (ESI): m / z 569.8 (M+H)+. Synthesis of compound 22-b At room temperature, 22-c (140 mg, 0.25 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (164 mg, 0.32 mmol), cataCXium A Pd G3 ( 18 mg, 0.03 mmol), potassium phosphate (157 mg, 0.74 mmol), THF (2 mL) and water (0.5 mL) were combined in a microwave tube. After degassed and purged with nitrogen, the reaction mixture was stirred at 65 °C overnight. The reaction mixture was concentrated and the residue was purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to afford compound 22-b (190 mg, 84%). LC-MS (ESI): m / z 919.7 (M+H)+. Synthesis of compound 22-a At room temperature, 22-b (190 mg, 0.21 mmol) and acetonitrile (5 mL) were added to a reaction flask. After degassed and purged with nitrogen, the above mixture was cooled down to 0 °C, and was added HCl / 1,4-dioxane (4.0 M, 1 mL). The reaction mixture was stirred at 0°C for 3 hours. The reaction mixture was concentrated at low temperature to give the crude compound 22-a (230 mg). LC-MS (ESI): m / z 775.5 (M+H)+. Synthesis of compound 22 To a reaction flask, crude compound 22-a (230 mg, 0.21 mmol), DMF (3 mL) and cesium fluoride (159 mg, 1.05 mmol) were added at room temperature. After degassed and purged with nitrogen, the reaction mixture was stirred at 60°C for 1 hour. The reaction mixture was filtered and the filtrate was purified by prep-HPLC to give compound 22 (23 mg, 18%). LC-MS (ESI): m / z 619.5 (M+H)+. Synthetic route of comparativecompound 1´ Synthesis of compound 1´-d At room temperature, 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (400 mg, 1.58 mmol), DCM (20 mL) were added to a reaction vial. After degassed and purged with nitrogen, the above mixture was cooled to -78°C in a dry ice-acetone bath and was added DIPEA (614 mg, 4.75 mmol) and hexamethyleneimine (141 mg, 1.42 mmol). After addition, the reaction mixture was naturally warmed to room temperature overnight. The reaction mixture was added with water, and the aqueous phase was extracted with DCM. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by column chromatography (mobile phase: PE / EA 10 / 0 to 6 / 4) to give compound 1´-d (390 mg, 78%). LC-MS (ESI): m / z 315.4 (M+H)+. Synthesis of compound 1´-c At room temperature, 1´-d (400 mg, 1.27 mmol), ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a- yl)methanol (404 mg, 2.54 mmol), 1,4-dioxane (10 mL) and DIPEA (656 mg, 5.08 mmol) were added to a reaction vial. After degassed and purged with nitrogen, the reaction mixture was stirred at 90 °C overnight. The reaction mixture was concentrated and the residue was purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to give compound 1´-c (450 mg, 81%). LC-MS (ESI): m / z 438.2 (M+H)+. Synthesis of compound 1´-b At room temperature, 1´-c (200 mg, 0.46 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (281 mg, 0.55 mmol), cataCXium A Pd G3 ( 33 mg, 0.05 mmol), potassium phosphate (291 mg, 1.37 mmol), THF (2 mL) and water (0.5 mL) were combined in a microwave tube. After degassed and purged with nitrogen, the reaction mixture was stirred at 65 °C overnight. The reaction mixture was concentrated and the residue was purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to give compound 1´-b (230 mg, 64%). LC-MS (ESI): m / z 789.0 (M+H)+. Synthesis of compound 1´-a At room temperature, 1´-b (230 mg, 0.29 mmol) and acetonitrile (5 mL) were added to a reaction flask. After degassed and purged with nitrogen, the above mixture was cooled down to 0 °C, and was added HCl / 1,4-dioxane (4.0 M, 1 mL). After addition, the reaction mixture was stirred at 0°C for 3 hours. The reaction mixture was concentrated at low temperature to give the crude compound 1´-a (270 mg). LC-MS (ESI): m / z 745.0 (M+H)+. Synthesis of comparative compound 1´ To a reaction flask, crude 1´-a (270 mg, 0.29 mmol), DMF (3 mL) and cesium fluoride (220 mg, 1.45 mmol) were added at room temperature. After degassed and purged with nitrogen, the reaction mixture was stirred at 60°C for 1 hour. The reaction mixture was filtered and the filtrate was purified by prep-HPLC to give compound 1´ (69 mg, 40%). LC-MS (ESI): m / z 588.7 (M+H)+. Example 21 Synthetic route of compound 23 Synthesis of compound 23-a To a solution of compound 12 (50 mg, 0.073 mmol) in dichloromethane (10 mL) was added isobutyryl chloride (16 mg, 0.146 mmol) and N,N-diisopropylethylamine (28 mg, 0.219 mmol) in an ice-water bath. The reaction mixture was stirred at this temperature for 1 hour. Water was added to the reaction mixture and the aqueous phase was extracted with dichloromethane (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to dryness to give compound 23-a (55 mg, 100%). The crude product was used directly in the next step without purification. LC-MS (ESI): m / z 759.9 (M+H)+. Synthesis of compound 23 To a solution of 23-a (55 mg, 0.072 mmol) in acetonitrile (8 mL) was added HCl / 1,4-dioxane (4 M, 1 mL) at room temperature and the reaction mixture was stirred at this temperature overnight. The reaction mixture was neutralized by adding saturated aqueous sodium bicarbonate solution and the aqueous phase was extracted with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness and the crude product was purified by prep-HPLC to give compound 23 (10.6 mg, 22%). LC-MS (ESI): m / z 659.3 (M+H)+. Example 22 Synthetic route of compound 24 Synthesis of compound 24-c To a solution of 3-b (160 mg, 0.38 mmol) in dichloromethane (15 mL) was added (2- methylenehexahydro-1H-pyrrolizin-7a-yl)methanol (88 mg, 0.58 mmol) in an ice-water bath, followed by slow addition of sodium tert-butoxide (111 mg, 1.15 mmol), and the mixture was stirred for 3 hours at this temperature. Water was added to the reaction mixture and the aqueous phase was extracted with dichloromethane (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness and the crude was purified by flash column chromatography (mobile phase: dichloromethane: methanol=10:1 / dichloromethane, 0-50%) to give compound 24-c (93 mg, 45%). LC-MS (ESI): m / z 533.8 (M+H)+. Synthesis of compound 24-b To a 10 mL microwave tube were added 24-c (93 mg, 0.17 mmol), ((6-fluoro-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylmethylsilyl)ethynyl)naphthalen-2- yl)oxy)triisopropylsilane (131 mg, 0.21 mmol), methanesulfonic acid [n-butylbis(1- adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (13 mg, 0.017 mmol), potassium phosphate (111 mg, 0.52 mmol), tetrahydrofuran (2.5 mL) and water (0.5 mL). After degassed and purged with nitrogen several times, the microwave tube was sealed. The reaction mixture was stirred at 65 °C overnight. Water was added to the reaction mixture and the aqueous phase was extracted with ethyl acetate (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to give compound 24-b (170 mg, 98%). The crude product was used directly for the next step without purification. LC-MS (ESI): m / z 996.7 (M+H)+. Synthesis of compound 24-a Cesium fluoride (130 mg, 0.85 mmol) was added to a solution of 24-b (170 mg, 0.17 mmol) in N,N- dimethylformamide (8 mL) at room temperature and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture and the aqueous phase was extracted with ethyl acetate (30 mL). The organic phase was washed twice with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness and the crude was purified by flash column chromatography (mobile phase: DCM: MeOH=10:1 / DCM, 0-50%) to give compound 24-a (70 mg, 60%). LC-MS (ESI): m / z 683.4 (M+H )+. Synthesis of compound 24 To a solution of 24-a (70 mg, 0.103 mmol) in acetonitrile (10 mL) was added hydrogen chloride / 1,4-dioxane (4 M, 1 mL) at room temperature and the reaction mixture was stirred at this temperature overnight. The reaction mixture was added saturated aqueous sodium bicarbonate to neutralize, and the aqueous phase was extracted with ethyl acetate (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness and the crude was purified by prep-HPLC to give compound 24 (8 mg, 13%). LC-MS (ESI): m / z 583.3 (M+H)+. Example 23 Synthetic route of compound 25 Referring to synthetic route of compounds 3 and 4，compound 25 was obtained using hexahydro- 1H-pyrrolizin-7a-yl methanol instead of ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a- yl)methanol . LC-MS (ESI): m / z 571.2 (M+H)+. Example 24 Synthetic route of compound 26 Synthesis of compound 26-d To a solution of 2,4-dichloro-7-bromoquinazoline (280 mg, 1.01 mmol) in tetrahydrofuran (15 mL) was added tert-butyl 1,2-diazepine-1-carboxylate (202 mg, 1.01 mmol) and N,N- diisopropylethylamine (390 mg, 3.02 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight. Water was added to the reaction mixture and the aqueous phase was extracted with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness and the crude was purified by flash column chromatography (mobile phase: ethyl acetate / petroleum ether, 0-30%) to give compound 26-d (440 mg, 99%). LC-MS (ESI): m / z 441.1 (M+H)+. Synthesis of compound 26-c To a solution of 26-d (440 mg, 0.10 mmol) in toluene (10 mL) was added ((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methanol (238 mg, 1.49 mmol) and sodium tert-butoxide (287 mg, 2.99 mmol) in an ice-water bath. The reaction temperature was warmed slowly to room temperature and stirred at this temperature overnight. The reaction mixture was concentrated to dryness, and the residue was added water and the aqueous phase was extracted with ethyl acetate (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness and the crude was purified by flash column chromatography (mobile phase: dichloromethane: methanol = 10:1 / dichloromethane, 0-100%) to give compound 26-c (538 mg, 96%). LC-MS (ESI): m / z 564.2 (M+H)+. Synthesis of compound 26-b To a 10 mL microwave tube were added 26-c (100 mg, 0.18 mmol), ((6-fluoro-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylmethylsilyl)ethynyl)naphthalen-2- yl)oxy)triisopropylsilane (133 mg, 0.21 mmol), methanesulfonic acid [n-butylbis(1- adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (13 mg, 0.018 mmol), potassium phosphate (113 mg, 0.53 mmol), tetrahydrofuran (2.5 mL) and water (0.5 mL). After degassed and purged with nitrogen several times, the microwave tube was sealed. The reaction mixture was stirred at 65°C overnight. Water was added to the reaction mixture and the aqueous phase was extracted with ethyl acetate (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to dryness to give compound 26-b (215 mg). The crude product was used directly for the next step without purification. LC-MS (ESI): m / z 826.9 (M+H)+. Synthesis of compound 26-a To a solution of 26-b (215 mg, 0.26 mmol) in N,N-dimethylformamide (10 mL) was added cesium fluoride (395 mg, 2.60 mmol) at room temperature and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture and the aqueous phase was extracted with ethyl acetate (30 mL). The organic phase was washed twice with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness and the crude was purified by flash column chromatography (mobile phase: DCM: MeOH=10:1 / DCM, 0-100%) to give compound 26- a (83 mg, 48%). LC-MS (ESI): m / z 670.9 (M+ H)+. Synthesis of compound 26 To a solution of 26-a (83 mg, 0.12 mmol) in acetonitrile (10 mL) was added HCl / 1,4-dioxane (4 M, 0.5 mL) at room temperature and the reaction mixture was stirred at this temperature overnight. The reaction mixture was added saturated aqueous sodium bicarbonate solution to neutralize, the aqueous phase was extracted with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness and the crude was purified by prep-HPLC to give compound 26 (17.1 mg, 24%). LC-MS (ESI): m / z 570.2 (M+H)+;1H NMR (400 MHz, CDCl3): δ 8.89 (1H, dd, J = 26.8, 8.8 Hz), 7.64 – 7.55 (2H, m), 7.32 (1H, s), 7.22 – 7.05 (3H, m), 7.03 (1H, d, J = 7.2 Hz), 5.43 – 5.20 (1H ,m), 4.26 – 3.93 (5H, m), 3.35 – 2.97 (6H, m), 2.78 (1H, d, J = 4.4 Hz), 2.01 – 1.88 (6H, m), 1.78 – 1.62 (5H, m). Example 25 Synthetic route of compound 27

[0014] Synthesis of compound 27-b To a solution of 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (500 mg, 1.39 mmol) in acetonitrile (15 mL) was added HCl / 1,4-dioxane (4 M, 1.5 mL) in an ice-water bath. The mixture was stirred at this temperature for 1 h, then concentrated to dryness and the crude product was purified by flash column chromatography (mobile phase: EA / PE, 0-40%) to give compound 27-b (436 mg, 99%). LC-MS (ESI): m / z 317.0 (M+H)+. Synthesis of compound 27-a To a 10 mL microwave tube were added 26-c (70 mg, 0.12 mmol), 27-b (78 mg, 0.25 mmol), [n- butyl bis(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (9 mg, 0.012 mmol), potassium phosphate (79 mg, 0.37 mmol), tetrahydrofuran (2.5 mL) and water (0.5 mL). After degassed and purged with nitrogen several times, the microwave tube was sealed. The reaction mixture was stirred at 65 °C overnight. The reaction mixture was added water, and the aqueous phase was extracted with ethyl acetate (30 mL). The organic phase was washed twice with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness and the crude was purified by flash column chromatography (mobile phase: DCM: MeOH=10:1 / DCM, 0-100%) to obtain 27-a (79 mg, 95%). LC-MS (ESI): m / z 674.9 (M+ H)+. Synthesis of compound 27 To a solution of 27-a (79 mg, 0.12 mmol) in acetonitrile (10 mL) was added HCl / 1,4-dioxane (4 M, 0.5 mL) at room temperature and the reaction mixture was stirred at this temperature overnight. The reaction mixture was added saturated aqueous sodium bicarbonate solution to neutralize, extracted with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness and the crude was purified by prep-HPLC to give compound 27 (26.1 mg, 39%). LC-MS (ESI): m / z 574.2 (M+H)+. Example 26 Synthetic route of compound 28 Synthesis of compound 28-a To a 10 mL microwave tube were added 13-c (50 mg, 0.098 mmol), 27-b (47 mg, 0.15 mmol), [n- butylbis(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (7 mg, 0.01 mmol), potassium phosphate (63 mg, 0.30 mmol), potassium tetrahydrofuran (2.5 mL) and water (0.5 mL). After degassed and purged with nitrogen several times, the microwave tube was sealed. The reaction mixture was stirred at 65 °C overnight. Water was added to the reaction mixture and the aqueous phase was extracted with ethyl acetate (30 mL). The organic phase was washed twice with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness and the crude was purified by flash column chromatography (mobile phase: DCM: MeOH=10:1 / DCM, 0-100%) to give compound 28-a (56 mg, 86%). LC-MS (ESI): m / z 663.9 (M+ H)+. Synthesis of compound 28 To a solution of 28-a (56 mg, 0.084 mmol) in acetonitrile (10 mL) was added HCl / 1,4-dioxane (4 M, 1 mL) at room temperature, and the reaction mixture was stirred for 3 hours at this temperature, then was neutralized by adding saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness and the crude was purified by prep-HPLC to give compound 28 (4.2 mg, 9%). LC-MS (ESI): m / z 563.2 (M+H)+. Example 27 Synthetic route of compound 29

[0015] Synthesis of compound 29-c To a solution of 3-c (200 mg, 0.48 mmol) in dichloromethane (20 mL) was added (1- (morpholinomethyl)cyclopropyl)methanol (165 mg, 0.96 mmol), followed by slow addition of sodium tert-butoxide (231 mg, 2.40 mmol) in an ice-water bath. The temperature was slowly warmed to room temperature and stirred at room temperature overnight. Water was added and the aqueous phase was extracted with dichloromethane (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered. The organic phase was concentrated to dryness, and the crude was purified by flash column chromatography (mobile phase: dichloromethane: methanol = 10:1 / dichloromethane, 0-100%) to give compound 29-c (260 mg, 98%). LC-MS (ESI): m / z 551.8 (M+H)+. Synthesis of compound 29-b To a 10 mL microwave tube were added 29-c (100 mg, 0.18 mmol), ((6-fluoro-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylmethylsilyl)ethynyl)naphthalen-2- yl)oxy)triisopropylsilane (136 mg, 0.22 mmol), methanesulfonic acid [n-butylbis(1- adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (13 mg, 0.018 mmol), potassium phosphate (116 mg, 0.54 mmol), tetrahydrofuran (2.5 mL) and water (0.5 mL). After degassed and purged with nitrogen several times, the microwave tube was sealed. The reaction mixture was stirred at 65 °C overnight. Water was added to the reaction mixture and the aqueous phase was extracted with ethyl acetate (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain the crude product 29-b (180 mg, 98%). The crude product was used directly for the next step without purification. LC-MS (ESI): m / z 1013.9 (M+H)+. Synthesis of compound 29-a Cesium fluoride (270 mg, 1.78 mmol) was added to a solution of 29-b (180 mg, 0.18 mmol) in N,N- dimethylformamide (8 mL) at room temperature and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture and the aqueous phase was extracted with ethyl acetate (30 mL). The organic phase was washed twice with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness and the crude was purified by flash column chromatography (mobile phase: MeOH / DCM, 0-100%) to give compound 29-a (40 mg, 32%). LC-MS (ESI): m / z 701.9 (M+H)+. Synthesis of compound 29 To a solution of 29-a (40 mg, 0.057 mmol) in acetonitrile (10 mL) was added HCl / 1,4-dioxane (4M, 0.5 mL) at room temperature, and the reaction mixture was stirred for 3 hours at this temperature. The reaction mixture was added saturated aqueous sodium bicarbonate solution to neutralize, extracted with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness and the crude was purified by prep-HPLC to give compound 29 (1.1 mg, 3%). LC-MS (ESI): m / z 601.3 (M+H)+. Example 28 Synthetic route of compound 30 Synthesis of compound 30-a To a 10 mL microwave tube were added 20-d (50 mg, 0.11 mmol), 6-fluoro-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-amine (59 mg, 0.13 mmol), methanesulfonic acid [n-butylbis(1-adamantyl)phosphine] (2-amino- 1,1'-biphenyl-2- yl)palladium(II) (8 mg, 0.011 mmol), potassium phosphate (73 mg, 0.34 mmol), tetrahydrofuran (2.5 mL) and water (0.5 mL). After degassed and purged with nitrogen several times, the microwave tube was sealed, and the reaction mixture was stirred at 65°C overnight. Water was added to the reaction mixture and the aqueous phase was extracted with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness and the crude was purified by flash column chromatography (mobile phase: methanol / dichloromethane, 0-100%) to give compound 30-a (61 mg, 72%). LC-MS (ESI): m / z 744.5 (M+H)+. Synthesis of compound 30 To a solution of 30-a (61 mg, 0.082 mmol) in N,N-dimethylformamide (8 mL) was added cesium fluoride (125 mg, 0.82 mmol) at room temperature, and the mixture was stirred at room temperature for 2 h. Water was added to the reaction mixture and the aqueous phase was extracted with ethyl acetate (30 mL). The organic phase was washed once with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The crude was purified by prep-HPLC to give compound 30 (17 mg, 35%). LC-MS (ESI): m / z 588.2 (M+H)+. Example 29 Synthetic route of compound 31 Synthesis of compound 31-e Potassium tert-butoxide (203 mg, 1.81 mmol) was added to a solution of 2-(6-bromo-2,3- difluorophenyl)acetonitrile (400 mg, 1.72 mmol) in N,N-dimethylformamide (10 mL) under the protection of nitrogen, and the resulting mixture was stirred at room temperature for 30 min, and then was added ethoxycarbonyl isothiocyanate (237 mg, 1.81 mmol) dropwise. After the addition, the reaction mixture was continued stirring at room temperature for 1 hour, and then stirred at 100°C for 1 hour. The reaction mixture was poured into 50mL of water and stirred for 10 min, the solid was collected by filtration and dried to obtain 31-e (550mg, 93%). LC-MS (ESI): m / z 340.8(M-H) -;1H NMR (400MHz, DMSO-d6): δ 12.10 (1H, s), 7.68 (1H, dd, J =8.8, 4.8 Hz), 7.21 (1H, t, J = 8.8 Hz), 4.30 (2H, q, J = 7.2 Hz), 1.31 (3H, t, J = 7.2 Hz). Synthesis of compound 31-d 31-e (300 mg, 0.87 mmol) was dissolved in dimethyl sulfoxide (9 mL) , followed by addition of 5 M aqueous sodium hydroxide (9 mL, 45 mmol). The reaction mixture was stirred at 130 °C for 2 hours. The reaction mixture was poured into water and solids were precipitated, stirred for 30 min at room temperature and held still overnight. The next day, it was filtered, the solid was collected and dried to give compound 31-d (220 mg, 93%). LC-MS (ESI): m / z 268.9 (M-H)-. Synthesis of compound 31-c To a solution of 31-d (220 mg, 0.81 mmol) in tetrahydrofuran (20 mL) was added di-tert-butyl dicarbonate (531 mg, 2.43 mmol), N,N-diisopropylethylamine (524 mg, 4.06 mmol) and 4- dimethylaminopyridine (10 mg, 0.081 mmol) and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture and the aqueous phase was extracted with ethyl acetate (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness and the crude was purified by column chromatography (mobile phase: EA / PE, 0-20%) to give compound 31-c (232 mg, 77%). LC-MS (ESI): m / z 369.0(M-H)-. Synthesis of compound 31-b To a 30 mL microwave tube were added 31-c (50 mg, 0.13 mmol), bis-pinacol borate (171 mg, 0.67 mmol), [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (10 mg, 0.013 mmol), potassium acetate (66 mg, 0.673 mmol) and 1,4-dioxane (8 mL). After degassed and purged with nitrogen several times, the microwave tube was sealed, and the reaction mixture was stirred at 100°C under microwave conditions for 2 h. Water was added to the reaction mixture and the aqueous phase was extracted with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness and the crude was purified by column chromatography (mobile phase: EA / PE, 0-20%) to give compound 31-b (50 mg, 89%). LC-MS (ESI): m / z 417.1(M-H)-. Synthesis of compound 31-a 3-b (100 mg, 0.19 mmol), 31-b (86 mg, 0.21 mmol), dichloro[bis(diphenylphosphinophenyl)ether]palladium(II) (13 mg, 0.019 mmol), cesium carbonate (121 mg, 0.37 mmol), and toluene (4 mL) were added to a 10 mL microwave tube at room temperature. After degassed and purged with nitrogen several times, the microwave tube was sealed. The reaction mixture was stirred at 100 °C and stirred for 2 hours. The reaction mixture was concentrated to dryness, water was added and the aqueous phase was extracted with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness and the crude was purified by flash column chromatography (mobile phase: dichloromethane: methanol = 10:1 / dichloromethane, 0-100%) to give compound 31-a (75 mg, 51%). LC-MS (ESI): m / z 795.9 (M+H)+. Synthesis of compound 31 Trifluoroacetic acid (2 mL) was added to a solution of 31-a (75 mg, 0.094 mmol) in dichloromethane (8 mL) at room temperature and the reaction mixture was stirred for 2 h at this temperature. The reaction mixture was neutralized by adding saturated aqueous sodium bicarbonate solution to the reaction mixture and the aqueous phase was extracted with dichloromethane (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness and the crude was purified by reversed-phase over column (mobile phase: 5%-95%, water (10 mmol ammonium bicarbonate): acetonitrile) and Prep-TLC (eluent: dichloromethane: methanol = 10:1) to give compound 31 (15 mg, 27%). LC-MS (ESI): m / z 595.2 (M+H)+. Example 30 Synthetic route of compound 32 Synthesis of compound 32 Compound 30 (60 mg, 0.102 mmol) was dissolved in ethyl acetate (15 mL) and methanol (2 mL), followed by addition of Pd / C 10% (100 mg). After degassed and purged with hydrogen several times, the reaction mixture was stirred for 4 hours at room temperature. The Pd / C was removed by filtration. The organic phase was concentrated to dryness and the crude was purified by prep-HPLC to give compound 32 (5.5 mg, 9%). LC-MS (ESI): m / z 592.2 (M+H)+. Example 31 Synthetic route of compound 33

[0016] Synthesis of compounds 33-g At room temperature, compound 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin- 4(3H)-one (1.0 g, 3.57 mmol) was dissolved in anhydrous DMAc (10 mL), to which anhydrous methanol (2 mL), sodium methanol (386 mg, 7.14 mmol) were added sequentially. The reaction mixture was stirred under protection of nitrogen at 50oC for 2 hours. The reaction mixture was cooled in an ice-water bath and the pH was adjusted to 3 with 1 M hydrochloric acid solution, then 20 mL of water was added and a large amount of solid precipitated. The mixture was filtered and the filter cake was washed with water (10 mL*3), the solid was collected and lyophilized overnight to give compound 33-g (930 mg, 95%). LC-MS (ESI): m / z = 276.1 [M+H]+. Synthesis of compound 33-f Compound 33-g (930 mg, 3.37 mmol) was dissolved in 20 mL of anhydrous acetonitrile at room temperature, DIPEA (4.18 mL, 25.30 mmol), and phosphorus trichloride (4.15 mL, 44.53 mmol) were added to the above mixture. The reaction mixture was stirred at 80 °C under protection of nitrogen for 1 hour. The reaction mixture was cooled to room temperature, concentrated at reduced pressure and the residue was purified by flash column chromatography (EA / PE= 0-30%) to give compound 33-f (775 mg, 78%). LC-MS (ESI): m / z = 293.9[M+H]+. Synthesis of compound 33-e Compound 33-f (775 mg, 2.63 mmol) was dissolved in 50 mL of dichloromethane at room temperature, to which DIPEA (1.31 mL, 7.91 mmol) and tert-butyl 1,2-diazepine-1-carboxylate (528 mg, 2.64 mmol) were added in an ice-water bath. The reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was added 50 mL of water, and the aqueous phase was extracted with dichloromethane (100 mL*2). The organic phase was washed sequentially with 10% sodium bisulfate solution (100 mL*2), saturated sodium bicarbonate (100 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated at reduced pressure, and the residue was purified by a flash column chromatography (PE / EA=2:1) to afford compound 33-e ( 980 mg, 81%). LC-MS (ESI): m / z = 458.2[M+H]+. Synthesis of compound 33-d Compound 33-e (980 mg, 2.14 mmol) was dissolved in 30 mL of ethyl acetate at room temperature and m-chloroperoxybenzoic acid (1.13 g, 5.56 mmol) was added. The reaction mixture was stirred at room temperature under protection of nitrogen for 1 hour. The reaction mixture was added 100 mL of saturated sodium bicarbonate, and the aqueous phase was extracted with ethyl acetate (150 mL). The organic phase was washed with saturated sodium bicarbonate (100 mL) and brine (100 mL) sequentially, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated at reduced pressure, and the residue was purified by a flash column chromatography (PE / EA=2:1) to afford compound 33-d (479 mg, 46%). LC-MS (ESI): m / z = 490.2 [M+H]+. Synthesis of compound 33-c Compound 33-d (200 mg, 0.41 mmol) was dissolved in 20 mL of dichloromethane at room temperature, ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methanol (78 mg, 0.49 mmol) was added, followed by addition of sodium tert-butanolate (98 mg, 1.02 mmol) in an ice-water bath and the reaction mixture was stirred in an ice-water bath for 2 hour. The reaction mixture was added 50 mL of water, and the aqueous phase was extracted with dichloromethane (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated at reduced pressure, and the residue was purified by a flash column chromatography (EA / PE=0-100%) to give compound 33-c (128 mg, 55%). LC-MS (ESI): m / z = 569.5 [M+H]+. Synthesis of compound 33-b Compound 33-c (128 mg, 0.22 mmol), ((6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)oxy)triisopropylsilane(211 mg, 0.34 mmol), methanesulfonyloxy(diadamantyl-n-butylphosphino)-2'-amino-1,1'-biphenyl-2-yl)palladium(II) (33 mg, 0.045 mmol), potassium phosphate (143 mg, 0.68 mmol), THF (2.5 mL), and water (0.5 mL) were combined in a microwave tube. The mixture was degassed and purged with nitrogen for three times, sealed, and stirred at 65 °C for 18 hours. The mixture was cooled to room temperature, 50 mL of water was added, and the aqueous phase was extracted with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated at reduced pressure, and the residue was purified by a flash column chromatography (PE / EA, then DCM / MeOH = 10:1) to give compound 33-b (53 mg, 23%). LC-MS (ESI): m / z = 1031.4 [M+H]+. Synthesis of compound 33-a Compound 33-b (53 mg, 0.051 mmol) was dissolved in 5 mL of DMF at room temperature. Cesium fluoride (156 mg, 1.03 mmol) was added, and the mixture was stirred under protection of nitrogen for 8 h at room temperature. The reaction mixture was added 50 mL of water, and the aqueous phase was extracted with ethyl acetate (50 mL*2). The organic phase was washed with brine (100 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated at reduced pressure, and the residue was purified by a flash column chromatography (DCM / MeOH = 10:1) to give compound 33-a (30 mg, 82%). LC-MS (ESI): m / z = 719.0 [M+H]+. Synthesis of compound 33 Compound 33-a (30 mg, 0.042 mmol) was dissolved in 5 mL of formic acid at room temperature and the mixture was stirred under protection of nitrogen for 3 hours at room temperature. The reaction mixture was concentrated at reduced pressure and 20 mL of dichloromethane was added to the residue, which was concentrated at reduced pressure to give compound the crude product, which was purified by prep-HPLC (NH4HCO3) to give compound 33 (8.9 mg, 34%). LC- MS(ESI):m / z=619.3[MS+H]+. Example 32 Synthetic route of compound 34 Synthesis of compound 34-e To a solution of compound 3-c (500 mg, 1.20 mmol) in 30 mL of dichloromethane at room temperature was added [3-[[tert-butyl(dimethyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolozin- 8-yl]methanol (377 mg, 1.32 mmol), followed by addition of sodium tert-butanol (289 mg, 3.00 mmol) in an ice-water bath, and the reaction mixture was stirred for 3 hours in an ice-water bath. The reaction mixture was added 50 mL of water, and the aqueous phase was extracted with dichloromethane (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated at reduced pressure, and the residue was purified by a flash column chromatography (DCM / MeOH=10:1) to give compound 34-e (700 mg, 88%). Synthesis of compound 34-d A solution of tetrabutylammonium fluoride in tetrahydrofuran (2.10 mL, 2.10 mmol, 1 M) was added into a solution of compound 34-e (700 mg, 1.05 mmol) in 20 mL of anhydrous tetrahydrofuran in an ice-water bath, and the reaction mixture was stirred for 2.5 h at room temperature. The reaction mixture was concentrated at reduced pressure, the residue was dissolved in 100 mL of ethyl acetate, washed sequentially with water (100 mL), brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated at reduced pressure, and the residue was dried under vacuum overnight to obtain compound 34-d (579 mg, 100%). LC-MS (ESI): m / z = 551.1 [M+H]+. Synthesis of compound 34-c Compound 34-d (460 mg, 0.83 mmol) was dissolved in 30 mL of anhydrous tetrahydrofuran at room temperature, followed by addition of p-nitrophenyl chloroformate (505 mg, 2.50 mmol), triethylamine (406 uL, 2.92 mmol) sequentially, and the reaction mixture was stirred for 1 h at room temperature. P-nitrophenyl chloroformate (505 mg, 2.50 mmol) and triethylamine (406 uL, 2.92 mmol) were added and the mixture was stirred at room temperature for 1 hour. Again p-nitrophenyl chloroformate (505 mg, 2.50 mmol) and triethylamine (406 uL, 2.92 mmol) were added and the reaction mixture was stirred at room temperature for 1 hour. A solution of dimethylamine in tetrahydrofuran (8.35 mL, 16.70 mmol, 2M) was added to the reaction mixture and stirred for 18 hours. A solution of dimethylamine in tetrahydrofuran (5 mL) in tetrahydrofuran was then added every 1 hour until the completion of the reaction, with a total of three additions of a solution of dimethylamine in tetrahydrofuran. To the reaction mixture 100 mL of water was added, the aqueous phase was extracted with ethyl acetate (100 mL). The organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated at reduced pressure, and the residue was purified by a flash column chromatography (DCM / MeOH=30:1-10:1) to give compound 34-c (240 mg, 47%). LC-MS (ESI): m / z = 622.3 [M+H]+. Synthesis of compound 34-b Compound 34-c (240 mg, 0.39 mmol), ((6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)oxy)triisopropylsilane (362 mg, 0.58 mmol), methylsulfonyloxy(di adamantyl-n-butylphosphino)-2'-amino-1,1'-biphenyl-2-yl)palladium(II) (56 mg, 0.077 mmol), potassium phosphate (246 mg, 1.16 mmol), THF (5 mL), and water (1 mL) were combined in a microwave tube. The mixture was degassed and purged with nitrogen for three times, sealed, and stirred for 18 hours at 65 °C. The mixture was cooled to room temperature, was added 100 mL of water and the aqueous phase was extracted with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated at reduced pressure, and the residue was purified by a flash column chromatography (DCM / MeOH=10:1) to give the crude compound 34-b (418 mg, as a mixture). LC-MS (ESI): m / z = 928.4 [M+H，de-TIPS]+; LC-MS (ESI): m / z = 1084.5 [M+H]+. Synthesis of compound 34-a Compound 34-b (418 mg, 0.39 mmol) was dissolved in 30 mL of DMF at room temperature, followed by addition of cesium fluoride (1.17 g, 7.71 mmol), and the mixture was stirred at room temperature under protection of nitrogen for 3.5 hours. The reaction mixture was added 100 mL of water, and the aqueous phase was extracted with ethyl acetate (100 mL). The organic phase was washed with brine (100 mL*5), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated at reduced pressure, and the residue was purified by a flash column chromatography (DCM / MeOH = 10:1) to give compound 34-a (266 mg, 88%). LC-MS (ESI). m / z = 772.4 [M+H]+. Synthesis of compound 34 Compound 34-a (100 mg, 0.13 mmol) was dissolved in 15 mL of formic acid at room temperature and the mixture was stirred at room temperature under protection of nitrogen for 18 hours. The reaction mixture was concentrated at reduced pressure, 50 mL of saturated sodium bicarbonate was added to the residue and the aqueous phase was extracted with dichloromethane (50 mL*2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated at reduced pressure to obtain the crude product, which was purified by a flash column chromatography (DCM / MeOH=10:1) to give compound 34 (25 mg, 29%). LC-MS (ESI): m / z=672.2[MS+H]+. Example 33 Synthetic route of compound 35 Synthesis of compound 35-a To a sealed tube at room temperature was added 3-b (150 mg, 0.28 mmol), 2-(8-chloro-3- (methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (146 mg, 0.42 mmol), cataCXium A Pd G3 (20 mg, 0.03 mmol), potassium phosphate ( 177 mg, 0.83 mmol), THF (2 mL) and water (0.5 mL). After degassed and purged with nitrogen, the reaction mixture was stirred at 65°C overnight. The reaction mixture was concentrated and the residue was purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to afford compound 35-a (160 mg, 79%). LC-MS (ESI): m / z 725.8 (M+H)+. Synthesis of compound 35 At room temperature, to a reaction vial were added 35-a (130 mg, 0.18 mmol), acetonitrile (5 mL). After degassed and purged with nitrogen, the reaction mixture was cooled to 0 °C and was added HCl / 1,4-dioxane (4.0 M, 1 mL), then stirred at room temperature for 3 hours. The reaction mixture was concentrated at room temperature and the residue was purified by prep-HPLC to give compound 35 (16 mg, 15%). LC-MS (ESI): m / z 581.7 (M+H)+. Example 34 Synthetic route of compound 36 Synthesis of compound 36-b To the sealed tube at room temperature were added 3-b (200 mg, 0.37 mmol), triisopropyl((6- (methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)silane (275 mg, 0.55 mmol), cataCXium A Pd G3 (54 mg, 0.07 mmol), potassium phosphate (236 mg, 1.11 mmol), THF (2 mL) and water (0.5 mL). After degassed and purged with nitrogen, the reaction mixture was stirred at 65°C overnight. The reaction mixture was concentrated and the residue was purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to afford compound 36-b (300 mg, 93%). LC-MS (ESI): m / z 871.9 (M+H)+. Synthesis of compound 36-a 36-b (140 mg, 0.16 mmol), DMF (2 mL), and cesium fluoride (244 mg, 1.61 mmol) were added to a reaction flask at room temperature. After degassed and purged with nitrogen, the reaction mixture was stirred at 60°C for 1 hr. The reaction mixture was added with water, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with water, dried over anhydrous sodium sulfate, and concentrated to give the crude compound 36-a (115 mg). LC-MS (ESI): m / z 715.8 (M+H)+. Synthesis of compound 36 At room temperature, to a reaction flask were added crude compound 36-a (115 mg, 0.16 mmol), acetonitrile (5 mL). After degassed and purged with nitrogen, the above mixture was cooled down to 0 °C, and was added HCl / 1,4-dioxane (4.0 M, 1 mL), then stirred at room temperature for 3 hours. The reaction mixture was neutralized with aqueous sodium bicarbonate and extracted by DCM. The organic phases were combined, washed with water, dried over anhydrous sodium sulfate, concentrated and the residue was purified by prep-HPLC to give compound 36 (11 mg, 12%). LC- MS (ESI): m / z 571.6 (M+H)+;1H NMR (400MHz, DMSO-d6): δ 10.24 (1H, s), 10.12 (1H, m), 7.92-7.81 (1H, d, J =8.0 Hz ), 7.49-7.36 (2H, m), 7.36-7.26 (1H, d, J =2.4 Hz ), 7.14-7.04 (1H, d, J =2.0 Hz ), 5.92-5.78 (1H, t, J =6.0 Hz ), 5.40-5.13 (1H, d, J =54.0 Hz), 4.18-3.88(4H, m), 3.56 (1H, s), 3.17-2.95 (5H, m), 2.90-2.75 (1H, m), 2.19-1.54 (12H, m). Example 35 Synthetic route of compound 37 Synthesis of compound 37-c At room temperature, to a reaction vial were added 3-c (400 mg, 0.96 mmol), (2,2- difluorohexahydro-1H-pyrrolizin-7a-yl)methanol (255 mg, 1.44 mmol), 1,4-dioxane (10 mL), DIPEA (373 mg, 2.89 mmol). After degassed and purged with nitrogen, the reaction mixture was stirred at 90°C overnight. The reaction mixture was concentrated and the residue was purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to give compound 37-c (300 mg, 56%). LC-MS (ESI): m / z 557.7 (M+H)+. Synthesis of compound 37-b 37-c (300 mg, 0.54 mmol), ((6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5- ((triisopropylmethylsilyl)ethynyl)naphthalen-2-yl)oxy)triisopropylsilane (505 mg, 0.81 mmol) were added to a sealed tube at room temperature, followed by combination of cataCXium A Pd G3 (78 mg, 0.11 mmol), potassium phosphate (343 mg, 1.62 mmol), THF (2 mL) and water (0.5 mL) in the sealed tube. After degassed and purged with nitrogen, the reaction mixture was stirred at 65°C overnight. The reaction mixture was concentrated and the residue was purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to give compound 37-b (460 mg, 84%). Synthesis of compound 37-a At room temperature, to a reaction vial were added 37-b (460 mg, 0.45 mmol), DMF (2 mL), and cesium fluoride (684 mg, 4.50 mmol). After degassed and purged with nitrogen, the reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was added water and the aqueous phase was extracted by EA. The organic phases were combined, washed with water, dried over anhydrous sodium sulfate and concentrated to give the crude compound 37-a (500 mg). LC-MS (ESI): m / z 707.7 (M+H)+. Synthesis of compound 37 At room temperature, to a reaction vial were added crude compound 37-a (500 mg, 0.45 mmol), DCM (10 mL) and TFA (3 mL). After stirred at room temperature for 2 hours, the reaction mixture was neutralized with aqueous sodium bicarbonate and the aqueous phase was extracted with DCM:MeOH=10:1 solution. The organic phases were combined, washed with water, dried over anhydrous sodium sulfate, concentrated and the residue was purified by prep-HPLC to give compound 37 (4.5 mg, 2%). LC-MS (ESI): m / z 607.5 (M+H)+. Example 36 Synthetic route of compound 38

[0017] Synthesis of compound 38-g NBS (2150 mg, 12.08 mmol), acetonitrile (28 mL), water (7 mL) and 5-bromo-1-pentene (1500 mg, 10.07 mmol) were added to a reaction vial at room temperature. The reaction mixture was stirred at room temperature for 36 hours.90 mL of water was added to the reaction mixture and the aqueous phase was extracted with DCM three times. The organic phases were combined, washed with water, brine, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by column chromatography (mobile phase: PE / EA 10 / 0 to 10 / 2) to give compound 38-g (800 mg, 32%). Synthesis of compound 38-f At room temperature, to a reaction vial were added 2-(tert-butyl)hydrazine-1,2-dicarboxylic acid-1- benzyl ester (780 mg, 2.93 mmol) and DMF (25 mL). After degassed and purged with nitrogen, the above mixture was added NaH (60%, 234 mg, 5.85 mmol) in batches in an ice-water bath and warmed to room temperature with stirring for 1 hour. A solution of 38-g (800 mg, 3.25 mmol) in DMF (10 mL) was added dropwise in an ice-water bath. After addition, the reaction mixture was warmed to room temperature overnight. The reaction mixture was quenched with saturated aqueous ammonium chloride and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with water, dried, concentrated, and the residue was purified by column chromatography (mobile phase: PE / EA 10 / 0 to 10 / 2) to give compound 38-f (500 mg, 49%). LC- MS (ESI): m / z 351.2 (M+H)+. Synthesis of compounds 38-e-1, 38-e-2 38-f (1000 mg, 2.85 mmol), EA (100 mL) and Pd / C (10%, 200 mg) were added to a reaction vial at room temperature. The reaction mixture was degassed and purged with hydrogen, then stirred under atmosphere of hydrogen for 2 hours at room temperature. The reaction mixture was filtered, and the filtrate was concentrated and the residue was purified by column chromatography (mobile phase: PE / EA 10 / 0 to 1 / 1) to give compounds 38-e-1 (350 mg, 57%) and 38-e-2 (180 mg, 29%). LC-MS (ESI): m / z 217.1 (M+H)+. Synthesis of compound 38-d 2,4,7-Trichloro-8-fluoropyrido[4,3-d]pyrimidine (2066 mg, 8.18 mmol) and DCM (30 mL) were added to a reaction vial at room temperature. After degassed and purged with nitrogen, the above mixture was cooled to -78°C in a dry ice-acetone bath, then was added DIPEA (2116 mg, 16.37 mmol) and 38-e-1 (590 mg, 2.73 mmol). After addition, the mixture was naturally warmed to room temperature and stirred overnight. Water was added to the reaction mixture, and the aqueous phase was extracted with DCM. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by column chromatography (mobile phase: PE / EA 10 / 0 to 7 / 3) to give compound 38-d (620 mg, 53%). Synthesis of compound 38-c At room temperature, to a reaction vial were added 38-d (300 mg, 0.69 mmol), ((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methanol (221 mg, 1.39 mmol), 1,4-dioxane (10 mL) and DIPEA (269 mg, 2.08 mmol). After degassed and purged with nitrogen, the reaction mixture was stirred at 90°C overnight. The reaction mixture was concentrated and the residue was purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to give compound 38-c (220 mg, 57%). LC-MS (ESI): m / z 555.9 (M+H)+. Synthesis of compound 38-b To a sealed tube at room temperature were added 38-c (220 mg, 0.40 mmol), ((6-fluoro-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylmethylsilyl)ethynyl)naphthalen-2- yl)oxy)triisopropylsilane (372 mg, 0.60 mmol), cataCXium A Pd G3 (58 mg, 0.08 mmol), potassium phosphate (252 mg, 1.19 mmol), THF (2 mL), and water (0.5 mL). After degassed and purged with nitrogen, the reaction mixture was stirred at 65°C overnight. The reaction mixture was concentrated and the residue was purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to give compound 38-b (230 mg, 57%). LC-MS (ESI): m / z 1018.0 (M+H)+. Synthesis of compound 38-a 38-b (230 mg, 0.23 mmol), DMF (2 mL), and cesium fluoride (343 mg, 2.26 mmol) were added to a reaction vial at room temperature. After degassed and purged with nitrogen, the reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was added water and the aqueous phase was extracted by EA. The organic phases were combined, washed with water, dried over anhydrous sodium sulfate and concentrated to give the crude compound 38-a (300 mg). LC-MS (ESI): m / z 705.9 (M+H)+. Synthesis of compound 38 At room temperature, to a reaction vial were added crude compound 38-a (300 mg, 0.23 mmol), DCM (6 mL) and TFA (2 mL). After stirred at room temperature for 1.5 hours, the reaction mixture was neutralized with aqueous sodium bicarbonate and the aqueous phase was extracted with DCM:MeOH=10:1 solution. The organic phases were combined, washed with water, dried over anhydrous sodium sulfate, concentrated and the residue was purified by prep-HPLC to give compound 38 (27 mg, 20%). LC-MS (ESI): m / z 605.5 (M+H)+. Example 37 Synthetic route of compound 39 Synthesis of compound 39-d At room temperature, to a reaction vial were added 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (1471 mg, 5.83 mmol) and DCM (30 mL). After degassed and purged with nitrogen, the above mixture was cooled to -78°C in a dry ice-acetone bath, the above mixture was added DIPEA (1506 mg, 11.65 mmol) and 38-e-2 (420 mg, 1.94 mmol). After addition, the mixture was naturally warmed to room temperature and stirred overnight. Water was added to the reaction mixture, the aqueous phase was extracted with DCM. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by column chromatography (mobile phase: PE / EA 10 / 0 to 7 / 3) to give compound 39-d (600 mg, 71%). Synthesis of compound 39-c At room temperature, to a reaction vial were added 39-d (300 mg, 0.69 mmol), ((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methanol (221 mg, 1.39 mmol), 1,4-dioxane (10 mL) and DIPEA (359 mg, 2.78 mmol). After degassed and purged with nitrogen, the reaction mixture was stirred at 90 °C overnight. The reaction mixture was concentrated and the residue was purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to give compound 39-c (250 mg, 65%). LC-MS (ESI): m / z 555.9 (M+H)+. Synthesis of compound 39-b To a sealed tube at room temperature were added 39-c (250 mg, 0.45 mmol), ((6-fluoro-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylmethylsilyl)ethynyl)naphthalen-2- yl)oxy)triisopropylsilane (422 mg, 0.68 mmol), cataCXium A Pd G3 (66 mg, 0.09 mmol), potassium phosphate (287 mg, 1.35 mmol), THF (2 mL) and water (0.5 mL). After degassed and purged with nitrogen, the reaction mixture was stirred at 65 °C overnight. The reaction mixture was concentrated and the residue was purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to afford compound 39-b (260 mg, 57%). LC-MS (ESI): m / z 1017.9 (M+H)+. Synthesis of compound 39-a 39-b (260 mg, 0.26 mmol), DMF (2 mL) and cesium fluoride (388 mg, 2.56 mmol) were added to a reaction vial at room temperature. After degassed and purged with nitrogen, the reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was added water and the aqueous phase was extracted by EA. The organic phases were combined, washed with water, dried over anhydrous sodium sulfate and concentrated to give the crude compound 39-a (400 mg). LC-MS (ESI): m / z 705.9 (M+H)+. Synthesis of compound 39 At room temperature, to a reaction vial were added crude compound 39-a (400 mg, 0.26 mmol), DCM (6 mL) and TFA (2 mL). After stirred at room temperature for 1.5 hours, the reaction mixture was neutralized with aqueous sodium bicarbonate and the aqueous phase was extracted with DCM:MeOH=10:1 solution. The organic phases were combined, washed with water, dried over anhydrous sodium sulfate, concentrated and the residue was purified by prep-HPLC to give compound 39 (36 mg, 23%). LC-MS (ESI): m / z 605.8 (M+H)+. Example 38 Synthetic route of compound 40

[0018] Synthesis of compound 40-f To a solution of 2-(tert-butyl)hydrazine-1,2-dicarboxylic acid-1-benzyl ester (2 g, 7.51 mmol) in DMF (60 mL) was added 60% sodium hydrogen (0.75 g, 18.78 mmol) in batches. After addition, the mixture was stirred at room temperature for 1 h, then was added a solution of tert-butyl N,N- bis(2-chloroethyl)carbamate (1.82 g, 7.51 mmol) in DMF ( 6 mL) dropwise and the mixture was stirred at 80oC for 72 hours. The reaction mixture was cooled to room temperature, quenched with ice-cold water. The aqueous phase was extracted with ethyl acetate (100 mL*2), the combined organic phases were washed with brine (50 mL*3), dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and the residue was purified by column chromatography (mobile phase: ethyl acetate: petroleum ether = 0-20%) to give compound 40-f (0.7 g, 21%). LC-MS (ESI): m / z 453.3 (M+ NH4)+. Synthesis of compound 40-e To a solution of 40-f (850 mg, 1.95 mmol) in ethanol (50 mL) was added 10% Pd / C (208 mg, 0.19 mmol). After degassed and purged with hydrogen for three times, the mixture was stirred for 2 h at room temperature. Filtered, and the filtrate was concentrated to dryness. The residue was purified by column chromatography (mobile phase: ethyl acetate: petroleum ether = 0-30%) to give compound 40-e (506 mg, 86%). LC-MS (ESI): m / z 302.2 (M+H)+. Synthesis of compound 40-d To a solution of 40-e (500 mg, 1.66 mmol) and N,N-diisopropylethylamine (643 mg, 4.98 mmol) in dichloromethane (50 mL) was added 2,4,7-trichloro-8-fluoro-pyrido[4,3-d]pyrimidine (628 mg, 2.49 mmol) in an acetone-dry ice-water bath. The mixture was naturally warmed to room temperature and stirred overnight. The next day, water was added to the reaction mixture. The aqueous phase was extracted with dichloromethane (80 mL*2), the combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and the residue was purified by column chromatography (mobile phase: ethyl acetate: petroleum ether=0-20%) to give compound 40-d (742 mg, 86%). LC-MS (ESI): m / z 517.4 (M+H)+. Synthesis of compound 40-c To a solution of 40-d (740 mg, 1.43 mmol) in dichloromethane (15 mL) was added ((2R,7aS)-2- fluorohexahydro-1H-pyrrolozin-7a-yl)methanol (273 mg, 1.72 mmol) in an ice-water bath, followed by addition of sodium tert-butanolate (344 mg, 3.58 mmol), and the mixture was stirred for 1 h at this temperature. Then water was added and the aqueous phase was extracted with dichloromethane (80 mL*2), the combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and the crude was purified by column chromatography (mobile phase: dichloromethane: methanol=10:1 / dichloromethane, 0-30%) to give compound 40-c (751 mg, 82%). LC-MS (ESI): m / z 640.8 (M+H)+. Synthesis of compound 40-b To a microwave tube were added 40-c (100 mg, 0.16 mmol), ((6-fluoro-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-5-((triisopropylmethylsilyl)ethynyl)naphthalen-2- yl)oxy)triisopropylsilane (146 mg, 0.23 mmol), methanesulfonic acid [n-butylbis(1-adamantyl ) phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (11 mg, 0.016 mmol), potassium phosphate (99 mg, 0.47 mmol), tetrahydrofuran (10 mL) and water (1 mL). After degassed and purged with nitrogen for three times, the microwave tube was sealed and stirred at 65 °C overnight. The reaction mixture was concentrated to dryness, and the crude product was purified by column chromatography (mobile phase: dichloromethane: methanol = 10:1 / dichloromethane, 0-50%) to give compound 40- b-1 (123 mg, 71%), LC-MS (ESI): m / z 1103.0 (M+H)+, and 40-b-2 (40 mg, 27%, dropping one TIPS group), LC-MS (ESI): m / z 946.4 (M+H)+. Synthesis of compound 40-a To a mixture of 40-b-1 and 40-b-2 (163 mg, 0.15 mmol) was added formic acid (10 mL) at room temperature and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated to dryness, and the residue was added saturated sodium bicarbonate, extracted with ethyl acetate (50 mL*2). The organic phase was dried and concentrated to dryness to give compound 40-a (117 mg, 140%), which was used directly in the next step without purification. LC-MS (ESI): m / z 746.4 (M+H)+. Synthesis of compound 40 Cesium fluoride (238 mg, 1.57 mmol) was added to a solution of 40-a (117 mg, 0.16 mmol) in N,N- dimethylformamide (10 mL) at room temperature and the mixture was stirred at room temperature overnight. A large amount of The reaction mixture was poured water, and the aqueous phase was extracted with ethyl acetate (50 mL*2). The organic phase was washed with brine (50 mL*3), concentrated to dryness, and the residue was purified by prep- HPLC (ammonium bicarbonate) to give compound 40 (23 mg, 25%). LC-MS (ESI): m / z 590.2 (M+H)+. Example 39 Synthetic route of compound 41 Synthesis of compound 41-d To a solution of 7-bromo-2,4,6-trichloro-8-fluoroquinazoline (1 g, 3.03 mmol) and N,N- diisopropylethylamine (1173 mg, 9.08 mmol) in tetrahydrofuran (50 mL) in an ice-water bath was added tert-butyl 1,2-diazepine-1-carboxylate (606 mg, 3.03 mmol), and the mixture was naturally warmed to room temperature and stirred overnight. The next day, water was added to the reaction mixture and the aqueous phase was extracted with ethyl acetate (100 mL*2). The combined organic phases were washed with brine (10 mL*2), dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and the residue was purified by column chromatography (mobile phase: ethyl acetate: petroleum ether=0-10%) to give compound 41-d (1350 mg, 90%). LC-MS (ESI): m / z 493.1 (M+H)+. Synthesis of compound 41-c To a solution of 41-d (300 mg, 0.61 mmol) in dichloromethane (30 mL) was added ((2R,7aS)-2- fluorohexahydro-1H-pyrrolozin-7a-yl)methanol (232 mg, 1.46 mmol) in an ice-water bath, followed by slow addition of sodium tert-butanolate (146 mg, 1.52 mmol), and the reaction mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture and the aqueous phase was extracted with dichloromethane (80 mL*2). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and the crude was purified by column chromatography (mobile phase: ethyl acetate: petroleum ether=0- 100%) to give compound 41-c (176 mg, 47%). LC-MS (ESI): m / z 616.2 (M+H)+. Synthesis of compound 41-b To a microwave tube were added 41-c (80 mg, 0.13 mmol), ((6-fluoro-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-5-((triisopropylmethylsilyl)ethynyl)naphthalen-2- yl)oxy)triisopropylsilane (162 mg, 0.26 mmol), palladium tetratriphenylphosphine (15 mg. 0.013 mmol), sodium carbonate (41 mg, 0.39 mmol), 1,4-dioxane (15 mL) and water (1.5 mL). After degassed and purged with nitrogen for three times, the microwave tube was sealed, stirred at 100 °C overnight. The reaction mixture was concentrated to dryness and the crude product was purified by column chromatography (mobile phase: dichloromethane: methanol = 10:1 / dichloromethane, 0-100%) to give compound 41-b (40 mg, 35%). LC-MS (ESI): m / z 878.3 (M+H)+. Synthesis of compound 41-a To a solution of 41-b (40 mg, 0.046 mmol) in N,N-dimethylformamide (6 mL) was added cesium fluoride (69 mg, 0.46 mmol) at room temperature, and the mixture was stirred for 1 h at room temperature. A large amount of The reaction mixture was poured water, the aqueous phase was extracted with ethyl acetate (50 mL*2). The organic phase was washed with brine (30 mL*3), concentrated to dryness, and the residue was purified by column chromatography (mobile phase: dichloromethane: methanol=10:1 / dichloromethane, 0-100%) to give compound 41-a (13 mg, 40%). LC-MS (ESI): m / z 722.3 (M+H)+. Synthesis of compound 41 To 41-a (13 mg, 0.018 mmol) was added formic acid (6 mL) at room temperature and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated to dryness at room temperature, purified by prep-HPLC (ammonium bicarbonate) and lyophilized to give compound 41 (2.5 mg, 22%). LC-MS (ESI): m / z 622.2 (M+H)+. Example 40 Synthetic route of compound 42 Synthesis of compound 42-a To a microwave tube were added 41-c (100 mg, 0.16 mmol), tert-butyl (3-cyano-4-(5,5-dimethyl- 1,3,2-dioxaborinan-2-yl)-7-fluorobenzo[b]thiophen-2-yl)carbamate (197 mg, 0.49 mmol), bis(diphenylphosphine phenyl ether) palladium(II) dichloride (12 mg, 0.016 mmol), cesium carbonate (264 mg, 0.81 mmol) and toluene (15 mL). After degassed and purged with nitrogen for three times, the microwave tube was sealed, stirred at 100 ° C for 1.5 hours. The reaction mixture was concentrated to dryness and the crude product was purified by column chromatography (mobile phase: dichloromethane: methanol = 10:1 / dichloromethane, 0-60%) to give compound 42-a (153 mg, 96%). LC-MS (ESI): m / z 828.5 (M+H)+. Synthesis of compound 42 Trifluoroacetic acid (2 mL) was added to a solution of 42-a (50 mg, 0.060 mmol) in dichloromethane (6 mL) at room temperature and the mixture was stirred for 1 h at room temperature. The reaction mixture was concentrated to dryness, purified by prep-HPLC (ammonium bicarbonate) and lyophilized to give compound 42 (9 mg, 24%). LC-MS (ESI): m / z 628.5 (M+H)+;1H NMR (400M, CD3OD) δ 9.56(1H, d, J=1.6Hz), 7.21-7.15(1H, m), 7.02(1H, t, J=9.2Hz), 5.40-5.21(1H, m), 4.60(3H, bs), 4.32-4.06(4H, m), 3.39-2.96(6H, m), 2.42-2.08(3H, m), 2.05-1.94(4H, m), 1.94- 1.84(1H, m), 1.82-1.67(4H, m). Example 41 Synthetic route of compound 43 Synthesis of compound 43-a To a microwave tube were added 42-a (140 mg, 0.17 mmol), methanesulfonic acid (2- dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-3-yl)palladium(II) (53 mg, 0.068 mmol), potassium phosphate (194 mg, 0.91 mmol), 1,4-dioxane ( 12 mL) and water (2 mL). After degassed and purged with nitrogen for three times, the microwave tube was sealed, and was added vinylboronic acid pinacol ester (135 mg, 0.88 mmol) by syringe, then stirred at 150 °C for 45 min. The reaction mixture was concentrated to dryness and the crude product was purified by column chromatography (mobile phase: dichloromethane: methanol = 10:1 / dichloromethane, 0-100%) to afford compound 43-a (110 mg, 79%) as a mixture of compounds with 2 Boc, 1 Boc and no Boc. Synthesis of compound 43 Trifluoroacetic acid (3 mL) was added to a solution of 43-a (70 mg, 0.085 mmol) in dichloromethane (9 mL) at room temperature, and the mixture was stirred for 1 h at room temperature. The reaction mixture was concentrated to dryness, dissolved in methanol, neutralized to pH 8 with saturated sodium bicarbonate solution, concentrated to dryness, and the residue was purified by column chromatography (mobile phase: ammonia methanol: dichloromethane = 0-10%) to give compound 43 (30 mg, 57%). LC-MS (ESI): m / z 620.5 (M+H)+. Example 42 Synthetic route of compound 44 Synthesis of compound 44 To a solution of 43 (25 mg, 0.040 mmol) in ethanol (20 mL) was added 10% Pd / C (22 mg, 0.020 mmol) at room temperature. After degassed and purged with hydrogen for three times, the mixture was stirred for 4 h at room temperature. The reaction mixture was filtered and the filtrate was concentrated to dryness, purified by prep-HPLC (ammonium bicarbonate) and lyophilized to give compound 44 (9 mg, 36%). LC-MS (ESI): m / z 622.8 (M+H)+;1H NMR (400M, CD3OD) δ 9.29(1H, s), 7.18-7.11(1H, m), 7.05-6.97(1H, m), 5.41-5.21(1H, m), 4.32-4.05(4H, m), 3.39-2.97(6H, m), 2.56-2.09(5H, m), 2.06-1.66(9H, m), 1.07(3H, t, J=7.6Hz). Example 43 Synthetic route of compound 45 Synthesis of compound 45-a A reaction vial charged with 42-a (100 mg, 0.12 mmol), potassium hydroxide (339 mg, 6.04 mmol), methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenylyl)(2'-amino-1,1'- biphenylyl-2-yl)palladium(II) (10 mg, 0.012 mmol), 1,4 -dioxane (20 mL), water (10 mL) was degassed and purged with nitrogen for three times, then stirred at 100 °C for 2 days. The reaction mixture was concentrated to dryness and the crude product was purified by column chromatography (mobile phase: dichloromethane: methanol=10:1 / dichloromethane, 0-100%) to give compound 45- a (17 mg, 17%). LC-MS (ESI): m / z 810.4 (M+H)+. Synthesis of compound 45 Trifluoroacetic acid (1 mL) was added to a solution of 45-a (17 mg, 0.021 mmol) in dichloromethane (3 mL) at room temperature and the mixture was stirred for 1 h at room temperature. The reaction mixture was concentrated to dryness, purified by prep-HPLC (ammonium bicarbonate) and lyophilized to give compound 45 (2 mg, 17%). LC-MS (ESI): m / z 610.3 (M+H)+. Example 44 Synthetic route of compound 46 Synthesis of compound 46-a To a reaction flask were added 29-c (160 mg, 0.29 mmol) and formic acid (10 mL) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated to dryness, the residue was added dichloromethane, and was adjusted to pH 8 with saturated sodium bicarbonate solution. The aqueous phase was extracted with dichloromethane (40 mL*2). The organic phase was concentrated to dryness and the residue was purified by column chromatography (mobile phase: methanol: dichloromethane = 0-10%) to give compound 46-a (97 mg, 74%). LC-MS (ESI): m / z 451.2 (M+H)+. Synthesis of compound 46 To a microwave tube were added 46-a (45 mg, 0.10 mmol), 27-b (47 mg, 0.15 mmol), [n- butylbis(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (7 mg, 0.01 mmol), potassium phosphate (106 mg, 0.50 mmol), tetrahydrofuran ( 15 mL) and water (1.5 mL). The reaction mixture was degassed and purged with nitrogen for three times, then sealed and stirred at 65 °C overnight. Water was added to the reaction mixture and the aqueous phase was extracted with ethyl acetate (50 mL*2), the combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated to dryness, purified twice by prep-HPLC (first trifluoroacetic acid, then ammonium bicarbonate), lyophilized to give compound 46 (5 mg, 8%). LC-MS (ESI): m / z 605.3 (M+H)+. Example 45 Synthetic route of compound 47 Synthesis of compound 47-d A reaction vial charged with [1-(aminomethyl)cyclopropyl]methanol (1 g, 9.89 mmol), acetonitrile (30 mL), 1,5-dibromopentane (2.39 g, 10.38 mmol) and potassium carbonate (3.56 g, 25.70 mmol) was stirred at room temperature overnight. The reaction mixture was concentrated to dryness and the residue was purified by column chromatography (mobile phase: ammonia methanol: dichloromethane = 0-10%) to give compound 47-d (1 g, 60%). LC-MS (ESI): m / z 170.2 (M+H)+. Synthesis of compound 47 Referring to compound synthetic route of cokpound 29, compound 47 (11 mg, 13%) was synthesized using 47-d instead of (1-(morpholinomethyl)cyclopropyl)methanol, with 3-c as material. LC-MS (ESI): m / z 599.3 (M+H)+. Example 46 Synthetic route of compound 48

[0019] Synthesis of compound 48-c To a solution of 7-bromo-2,4-dichloro-8-fluoro-6-(trifluoromethyl)quinazoline (1 g, 2.75 mmol) and N,N-diisopropylethylamine (1065 mg, 8.24 mmol) in tetrahydrofuran (50 mL) in an ice-water bath was added tert-butyl 1,2-diazepine-1-carboxylate (550 mg, 2.75 mmol). The mixture was naturally warmed to room temperature and stirred overnight. The next day, water was added and the aqueous phase was extracted with ethyl acetate (100 mL*2), the combined organic phases were washed with brine (10 mL*2), dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and purified on a silica column (mobile phase: ethyl acetate: petroleum ether=0-10%) to afford 48- c (1270 mg, 88%). LC-MS (ESI): m / z 527.1 (M+H)+. Synthesis of compound 48-b To a solution of 48-c (1200 mg, 2.27 mmol) in tetrahydrofuran (25 mL) and N,N- dimethylformamide (25 mL) at room temperature was added ((2R,7aS)-2-fluorohexahydro-1H- pyrrolizin-7a-yl)methanol (1086 mg, 6.82 mmol), cesium carbonate (2223 mg, 6.82 mmol) and DABCO (1020 mg, 9.10 mmol), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture and the aqueous phase was extracted with ethyl acetate (100 mL*2), the combined organic phases were washed with brine (50 mL*3), dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and the crude was purified by column chromatography (mobile phase: methanol: dichloromethane=0-10%) to give compound 48-b (649mg, 44%). LC-MS (ESI): m / z 650.3 (M+H)+. Synthesis of compound 48-a To a microwave tube were added 48-b (60 mg, 0.092 mmol), tert-butyl (3-cyano-4-(5,5-dimethyl- 1,3,2-dioxaborinan-2-yl)-7-fluorobenzo[b]thiophen-2-yl)carbamate (75 mg, 0.18 mmol), bis(diphenylphosphine phenyl ether)palladium(II) dichloride (7 mg, 0.0092 mmol), cesium carbonate (150 mg, 0.46 mmol) and toluene (10 mL). After degassed and purged with nitrogen for three times, the microwave tube was sealed, stirred at 100 ° C for 1.5 hours. The reaction mixture was concentrated to dryness and the crude product was purified by column chromatography (mobile phase: methanol: dichloromethane = 0-10%) to give compound 48-a (60 mg, 75%). LC-MS (ESI): m / z 862.6 (M+H)+. Synthesis of compound 48 Trifluoroacetic acid (2 mL) was added to a solution of 48-a (60 mg, 0.070 mmol) in dichloromethane (6 mL) at room temperature and the mixture was stirred for 2 hours at room temperature. The reaction mixture was concentrated to dryness, purified by prep-HPLC (ammonium bicarbonate) and lyophilized to give compound 48 (14 mg, 30%). LC-MS (ESI): m / z 662.2 (M+H)+;1H NMR (400 M, CD3OD) δ 9.93(1H, s), 7.22-7.15(1H, m), 7.03-6.95(1H, m), 5.41-5.19(1H, m), 4.60(1H, bs), 4.27(1H, d, J=10.4Hz), 4.23-4.06(3H, m), 3.27-2.95(5H, m), 2.41-2.08(3H, m), 2.06-1.67(9H, m). Example 47 Synthetic route of compound 49 Synthesis of compound 49-d A reaction vial charged with 7-bromo-2,4-dichloro-6,8-difluoroquinazoline (400 mg, 1.27 mmol), tetrahydrofuran (100 mL), DIPEA (444 mg, 3.44 mmol) and tert-butyl 1,2-diazepine-1-carboxylate (383 mg, 1.91 mmol) was stirred for 12 h at room temperature. The reaction mixture was concentrated at room temperature and saturated sodium bicarbonate solution (100 mL) was added to the residue. The aqueous phase was extracted with dichloromethane (100 mL*3). The organic phase was concentrated and the residue was purified by column chromatography (PE / EA=10 / 1) to give compound 49-d (396 mg, 65%). LC-MS (ESI): m / z = 477.6 (M+H)+. Synthesis of compound 49-c A reaction vial charged with 49-d (400 mg, 0.84 mmol), tetrahydrofuran (15 mL), DABCO (376 mg, 3.35 mmol), DMF (15 mL), ((2R,7aS)-2-fluorohexahydro-1H-pyrrolylazin-7a-yl)methanol (400 mg, 2.51 mmol), cesium carbonate (818 mg.2.51 mmol) was stirred overnight under protection of nitrogen. Water (20 mL) was added to the reaction mixture and the aqueous phase was extracted with ethyl acetate (50 mL*3). The organic phase was concentrated and the residue was purified by column chromatography (MeOH / DCM=1 / 10) to afford compound 49-c (380 mg, 76%). LC-MS (ESI): m / z = 600.1(M+H)+. Synthesis of compound 49-b A reaction vial charged with 49-c (100 mg, 0.17 mmol), 1,4-dioxane (3 mL), water (0.5 mL), ((6- fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5- ((triisopropylmethylsilyl)ethynyl)naphthalen-2-yl)oxy)triisopropylsilane (208 mg. 0.33 mmol), sodium carbonate (53 mg, 0.50 mmol) and palladium tetrakis(triphenylphosphine) (38 mg, 0.03 mmol) was degassed and purged with nitrogen for three times and the reaction mixture was stirred in an oil bath prestirred at 100oC for 12 hours. The reaction mixture was concentrated to dryness and the residue was purified by column chromatography (mobile phase: methanol / dichloromethane = 1 / 30; 1 / 10) to afford compound 49-b (79 mg, 55%). LC-MS (ESI): m / z = 862.5(M+H)+. Synthesis of compound 49-a To a reaction flask were added 49-b (79 mg, 0.09 mmol), DMF (6 mL) and cesium fluoride (230 mg, 1.51 mmol). The resulting mixture was stirred at room temperature for 6 hours, then was added water (50 mL), filtered, and the filter cake was dried to give compound 49-a (59 mg, 91%). LC-MS (ESI): m / z = 706.3 (M+H)+. Synthesis of compound 49 A reaction vial charged with 49-a (59 mg, 0.08 mmol) and formic acid (5 mL) was stirred at room temperature for 12 hours. The reaction mixture was concentrated at room temperature and saturated sodium bicarbonate (20 mL) was added to the residue and the aqueous phase was extracted with ethyl acetate (20 mL*3). The organic phase was concentrated and the residue was purified by prep- HPLC to afford compound 49 (20.6 mg, 41%), LC-MS (ESI): m / z 606.3(M+H)+;1H NMR (400 MHz, DMSO-d6): δ 10.21 (1H, s), 9.08 (1H, d, J =12.4 Hz), 7.98 (1H, t, J = 6.4 Hz), 7.48 (1H, t, J = 9.2 Hz), 7.40 (1H, s), 7.15 (1H, s), 5.68 (1H, t, J = 6.0Hz), 5.29 (1H, d, J = 54.8Hz), 4.16-3.90 (4H, m), 3.94 (1H,s), 3.18 – 2.95 (5H, m), 2.93 – 2.78 (1H, m), 2.25 – 2.00 (4H, m), 1.98 – 1.74 (5H, m), 1.73 – 1.60 (3H, m). Example 48 Synthetic route of compound 50 Synthesis of compound 50-c To a reaction flask were added 4-bromo-6-chloro-5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H- indazole (1000 mg, 2.27 mmol), 1,4-dioxane (12 mL), water (3 mL), ((Z)-1-propenyl)-pinacol ester of borate (500 mg, 2.98 mmol), potassium phosphate (1700 mg.8.01 mmol) and PdCl2(dppf)CH2Cl2(170 mg, 0.21 mmol). After degassed and purged with nitrogens for three times, the reaction flask was placed in an oil bath prestirred at 100oC and stirred for 3 hours. The reaction mixture was concentrated to dryness and the residue was purified by column chromatography (mobile phase: PE / EA=100 / 0; 100 / 5) to give compound 50-c (380 mg, 47%). Synthesis of compound 50-b To a reaction vial were added 50-c (360 mg, 1.01 mmol) and tetrahydrofuran (10 mL). The resulting mixture was stirred at -78oC for 10 min, then was slowly added n-Butyllithium solution (2.5M, 0.6mL, 1.50mmol) dropwise. After addition, the mixture was stirred at the same temperature for 30 minutes, then was slowly added isopropanol pinacol borate (283 mg, 1.52 mmol) and stirred at - 78oC for 60 minutes. Saturated ammonium chloride (30 mL) was added to the reaction mixture and the aqueous phase was extracted with ethyl acetate (20 mL*3). The organic phase was concentrated and the residue was purified by column chromatography (PE / EA=100 / 0; 100 / 3) to afford compound 50-b (210 mg, 52%). LC-MS (ESI): m / z 403.1(M+H)+. Synthesis of compound 50-a To a reaction flask were added 49-c (149 mg, 0.25 mmol), 1,4-dioxane (10 mL), water (2 mL), 50- b (100 mg, 0.25 mmol), cesium fluoride (113 mg, 0.75 mmol) and PdCl2(dtbpf) (30 mg, 0.05 mmol). After degassed and purged with nitrogen for three times, the reaction flask was placed in an oil bath pre-heated 100oC and stirred in for 2 hours. The reaction mixture was concentrated to dryness and the residue was purified by column chromatography (mobile phase: MeOH / DCM = 1 / 100; 1 / 10) to afford compound 50-a (180 mg, 91%). LC-MS (ESI): m / z = 796.4 (M+H)+. Synthesis of compound 50 A reaction vial charged with 50-a (80 mg, 0.10 mmol), dichloromethane (3 mL) and trifluoroacetic acid (1 mL) was stirred at room temperature for 3 hours. The reaction mixture was concentrated to dryness, and the residue was added saturated sodium bicarbonate (20 mL) and the aqueous phase was extracted with ethyl acetate (20 mL*3). The organic phase was concentrated and the residue was purified by column chromatography (mobile phase: DCM / MeOH=30 / 1; 10 / 1) to afford compound 50 (27.8 mg, 45%). LC-MS (ESI): m / z = 612.5 (M+H)+. Example 49 Synthetic route of compound 51 Synthesis of compounds 51-g A reaction vial charged with tert-butyl 4-(benzyloxy)-2-(methylsulfonyl)-5,8-dihydropyrido[3,4- d]pyrimidine-7(6H)-carboxylate (840 mg, 2.00 mmol), toluene (30 mL), ((2R,7aS)-2- fluorohexahydro-1H-pyrrolozin-7a-yl)methanol (383 mg, 2.40 mmol) and sodium tert-butoxide (289 mg, 3.00 mmol) was stirred at 0oC under protection of nitrogen atmosphere for 1 hour and continued stirring at room temperature for 1 hour. The reaction mixture was purified by column chromatography (mobile phase: methanol / dichloromethane 1 / 30 to 1 / 10) to afford compound 51-g (561 mg, 56%) LC-MS (ESI): m / z 499.8(M+H)+. Synthesis of compound 51-f A reaction vial charged with 51-g (560 mg, 1.12 mmol), toluene (6 mL), trifluoroacetic acid (0.86 mL, 11.23 mmol) was stirred at room temperature under atmosphere nitrogenfor 2 hours. The reaction mixture was added sodium hydroxide (2M, 10mL), was adjusted pH to 9.5-10, and the aqueous phase was extracted with EA (10mL*3). The organic phase was concentrated and the residue was purified by reversed-phase column under basic conditions to give compound 51-f (371 mg, 83%). LC-MS (ESI): m / z 399.7(M+H)+. Synthesis of compound 51-e To a reaction flask were added 51-f (500 mg, 1.25 mmol), ethanol (30 mL), Pd / C10% (100 mg, 10% content), and the reaction mixture was stirred at room temperature under hydrogen (1000 mL) for 3 hours. The reaction mixture was filtered, washed with ethanol (10 mL) and the filtrate was concentrated to give compound 51-e (260 mg, 67%). LC-MS (ESI): m / z 309.3 (M+H)+. Synthesis of compound 51-d A reaction vial charged with 51-e (180 mg, 0.58 mmol), toluene (15 mL), ((8-bromo-2-fluoro-6- (methoxymethoxy)naphthalen-1-yl)ethynyl)triisopropylsilane (331 mg, 0.72 mmol), sodium tert- butoxide (280 mg, 2.92 mmol), BINAP (73 mg, 0.12 mmol ) was stirred at room temperature under protection of nitrogen for 2 min, then was added Pd2(dba)3(53 mg, 0.06 mmol), and the mixture continued stirring at 110oC for 3 h under protection of nitrogen. The reaction mixture was added silica gel and purified directly by column chromatography (mobile phase: methanol / dichloromethane = 1 / 30, 1 / 10) to afford compound 51-d (232 mg, 57%). LC-MS (ESI): m / z 693.6 (M+H)+. Synthesis of compound 51-c To a reaction flask, 51-d (90 mg, 0.13 mmol), DMF (15 mL), cesium fluoride (395 mg, 2.60 mmol) were added and the mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered and washed with DMF (15 mL) to obtain a solution of 51-c in DMF which was directly used in the next step. LC-MS (ESI): m / z 537.5(M+H)+. Synthesis of compound 51-b To a reaction flask were added the solution of 51-c in DMF and Pd / C10% (12 mg, 10% content). The resulting was stirred at room temperature for 3 hours under hydrogen (1000 mL) atmosphere. The reaction mixture was filtered, quenched by adding water (50 mL) and the aqueous phase was extracted with ethyl acetate (30 mL*3). The organic phase was concentrated and the residue was purified by column chromatography (MeOH / DCM=1 / 100;1 / 10) to afford compound 51-b (57 mg, 81% overall yield in two steps). LC-MS (ESI): m / z 541.5(M+H)+. Synthesis of compound 51-a A reaction vial charged with 51-b (59 mg, 0.11 mmol), DMSO (5 mL), DIPEA (70 mg, 0.55 mmol) and N-bis(trifluoromethanesulfonyl)aniline (117 mg, 0.33 mmol) was stirred at room temperature for 2 hours. Then 1,2-diazepine dihydrochloride (50 mg, 0.29 mmol) and DIPEA (70 mg, 0.55 mmol) were added to DMSO (5 mL) and stirred for 30 min, and then this reaction mixture was added to the above mixture. The resulting mixture was stirred at 50oC under atmosphere of nitrogen for 5 hours. The reaction mixture was concentrated and water (30mL) was added. It was filtered and the filter cake was purified by column chromatography (MeOH / DCM=1 / 100; 1 / 10) to afford compound 51-a (50 mg, 74%), LC-MS (ESI): m / z 623.4(M+H)+. Synthesis of compound 51 A reaction vial charged with 51-a (45 mg, 0.07 mmol), dichloromethane (5 mL) was stirred for 10 min in an ice-water bath, then was added 2,2-bipyridine (200 mg, 0.82 mmol) and TMSOTf (200 mg, 0.90 mmol). Formic acid (5 mL) was slowly added dropwise to the mixture and the reaction mixture was warmed to room temperature under protection of nitrogen and stirred for 12 hours. The reaction mixture was concentrated at room temperature, was added saturated sodium bicarbonate solution (30 mL) and the aqueous phase was extracted with dichloromethane (30 mL*2). The organic phase was concentrated and the residue was purified by column chromatography (MeOH / DCM=1 / 10) to give compound 51 (7.1 mg, 17%). LC-MS (ESI): m / z 579.5(M+H)+. Example 50 Synthetic route of compound 52 Synthesis of compound 52 Referring to synthetic route of compound 29， compound 52 was synthesized using (1-((4- methylpiperazin-1-yl)methyl)cyclopropyl)methanol instead of (1- (morpholinomethyl)cyclopropyl)methanol and 3-c as material. LC-MS (ESI): m / z 614.3 (M+H)+. Example 51 Synthetic route of compound 53 Synthesis of compound 53 Referring to synthetic route of compound 29 ， replacement of (1- (morpholinomethyl)cyclopropyl)methanol with (1-(pyrrolidin-1-ylmethyl)cyclopropyl)methanol, and using 3-c as material to obtain compound 53. LC-MS (ESI): m / z 585.3 (M+H)+. Example 52 Synthetic route of compound 54 Synthesis of compound 54-b To a microwave tube were added 48-b (160 mg, 0.25 mmol), ((6-fluoro-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-5-((triisopropylmethylsilyl)ethynyl)naphthalen-2- yl)oxy)triisopropylsilane (461 mg, 0.74 mmol), Pd(DPEphos)Cl2( 35 mg, 0.049 mmol), cesium carbonate (401 mg, 1.23 mmol), toluene (15 mL). After degassed and purged with nitrogen for three times, the microwave tube was sealed, microwaved at 150oC, and stirred for 6 hours. The reaction mixture was concentrated to dryness and the residue was purified by column chromatography (mobile phase: methanol: dichloromethane = 0-5%) to give compound 54-b (60 mg, 23%). LC-MS (ESI): m / z 1068.5 (M+H)+. Synthesis of compound 54-a To a solution of 54-b (60 mg, 0.056 mmol) in N,N-dimethylformamide (10 mL) was added cesium fluoride (85 mg, 0.56 mmol) at room temperature and the mixture was stirred at room temperature overnight. The reaction mixture was poured a large amont of water and the aqueous phase was extracted with ethyl acetate (50 mL*2). The organic phase was washed with brine (30 mL*3), concentrated to dryness, and the residue was purified by column chromatography (mobile phase: dichloromethane: methanol: dichloromethane = 0-7%) to give compound 54-a (15 mg, 35%). LC- MS (ESI): m / z 756.7 (M+H)+. Synthesis of compound 54 A mixture of 54-a (15 mg, 0.020 mmol) and formic acid (6 mL) was stirred at room temperature overnight. The reaction mixture was concentrated to dryness at room temperature, purified by prep- HPLC (ammonium bicarbonate) and lyophilized to give compound 54 (3 mg, 23%). LC-MS (ESI): m / z 656.2 (M+H)+. Synthetic route of compound 55 Synthesis of compound 55-b To a sealed tube at room temperature was added 2-c (230 mg, 0.39 mmol), ((6-fluoro-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylmethylsilyl)ethynyl)naphthalen-2- yl)oxy)triisopropylsilane (366 mg, 0.59 mmol), cataCXium A Pd G3 (28 mg, 0.04 mmol), potassium phosphate (249 mg, 1.17 mmol), THF (2 mL) and water (0.5 mL). After degassed and purged with nitrogen, the reaction mixture was stirred at 65 °C overnight. The reaction mixture was concentrated and the residue was purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to give compound 55-b (280 mg, 68%). Synthesis of compound 55-a At room temperature, to a reaction vial were added 55-b (280 mg, 0.27 mmol), EA (30 mL) and Pd / C (10%, 200 mg). After degassed and purged with hydrogen, the reaction mixture was stirred under hydrogen protection for 2 hours at room temperature. The reaction mixture was filtered and the filtrate was concentrated to give compound 55-a (190 mg, 78%). LC-MS (ESI): m / z 917.9 (M+H)+. Synthesis of compound 55 55-a (190 mg, 0.21 mmol), DMF (3 mL) and cesium fluoride (315 mg, 2.07 mmol) were added to a reaction vial at room temperature. It was stirred at room temperature for 5 hours. The reaction mixture was filtered and the filtrate was purified by prep-HPLC to give compound 55 (55 mg, 44%). LC-MS (ESI): m / z 605.8 (M+H)+. Synthesis of compounds 55-1 and 55-2 compound 55（55 mg）was separated by chiral resolution to obtain compound 55-1（15mg，27%） and 55-2（19mg，35%）. Synthetic route of compound 56 Synthesis of compound 56-g Diethyl 2,2-difluoroglutarate (1000 mg, 4.46 mmol) and THF (10 mL) were added to a reaction flask at room temperature. After degassed and purged with nitrogen, the above mixture was cooled down to 0 °C, and was added a solution of lithium aluminum hydride (1 M, 11 mL, 11.00 mmol) in tetrahydrofuran dropwise. After the dropwise addition, the reaction mixture was naturally warmed to room temperature and stirred overnight. The reaction mixture was quenched with methanol (100 mL), was added sodium sulfate decahydrate (5 g) and stirred for 1 hour. The reaction mixture was filtered through celite and the filtrate was concentrated. The residue was added ethyl acetate, a solid precipitated, filtered and the filtrate was concentrated to give compound 56-g (550 mg, 88%). Synthesis of compound 56-f At room temperature, to a reaction vial were added 56-g (550 mg, 3.93 mmol), DCM (30 mL), triethylamine (1589 mg, 15.70 mmol) and p-toluenesulfonyl chloride (2245 mg, 11.78 mmol). After degassed and purged with nitrogen, the reaction mixture was stirred at room temperature overnight. Water was added to the reaction mixture and the aqueous phase was extracted with DCM. The organic phases were combined, washed with water, brine, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by column chromatography (mobile phase: PE / EA 10 / 0 to 6 / 4) to give compound 56-f (960 mg, 55%). LC-MS (ESI): m / z 466.7 (M+NH4)+. Synthesis of compound 56-e At room temperature, to a reaction vial were added 56-f (500 mg, 1.12 mmol), acetonitrile (30 mL), 2-(tert-butyl)hydrazine-1,2-dicarboxylic acid-1-benzyl ester (297 mg, 1.12 mmol) and cesium carbonate (1816 mg, 5.57 mmol). After degassed and purged with nitrogen, the reaction mixture was stirred at 65°C for 36 hours. The reaction mixture was filtered, and the filtrate was concentrated and the residue was purified by column chromatography (mobile phases: PE / EA 10 / 0 to 7 / 3) to give compound 56-e (230 mg, 56%). LC-MS (ESI): m / z 388.4 (M+NH4)+. Synthesis of compound 56-d 56-e (230 mg, 0.62 mmol), EA (25 mL) and Pd / C (10%, 100 mg) were added to a reaction vial at room temperature. The reaction mixture was degassed and purged with hydrogen for 4 hours at room temperature. The reaction mixture was filtered, and the filtrate was concentrated and the residue was added acetonitrile (10 mL) and HCl / 1,4-dioxane (1M, 2 mL, 2.00 mmol). The reaction mixture was stirred at room temperature After degassed and purged with nitrogen for 2 hours, the reaction mixture was concentrated to give the crude compound 56-d (150 mg). LC-MS (ESI): m / z 137.2 (M+1)+. Synthesis of compound 56-c At room temperature, to a reaction vial were added 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (313 mg, 1.24 mmol), DCM (15 mL) and crude compound 56-d (150 mg, 0.62 mmol). The mixture was degassed and purged with nitrogen, cooled to 0°C, and was added DIPEA (481 mg, 3.72 mmol). The mixture was naturally warmed to room temperature and stirred overnight. Water was added to the reaction mixture and the aqueous phase was extracted with DCM. The organic phases were combined, dried, concentrated and the residue was purified by column chromatography (mobile phase: PE / EA 10 / 0 to 6 / 4) to give compound 56-c (110 mg, 50%). LC-MS (ESI): m / z 352.1 (M+H)+. Synthesis of compound 56-b At room temperature, to a reaction vial were added 56-c (110 mg, 0.31 mmol), ((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methanol (99 mg, 0.62 mmol), 1,4-dioxane (5 mL) and DIPEA (162 mg, 1.25 mmol). After degassed and purged with nitrogen, the reaction mixture was stirred at 90 °C overnight. The reaction mixture was concentrated and the residue was purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to give compound 56-b (80 mg, 54%). LC-MS (ESI): m / z 475.9 (M+H)+. Synthesis of compound 56-a To a sealed tube at room temperature was added 56-b (80 mg, 0.17 mmol), ((6-fluoro-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylmethylsilyl)ethynyl)naphthalen-2- yl)oxy)triisopropylsilane (158 mg, 0.25 mmol), cataCXium A Pd G3 (25 mg, 0.03 mmol), potassium phosphate (107 mg, 0.50 mmol), THF (2 mL) and water (0.5 mL). After degassed and purged with nitrogen, the reaction mixture was stirred at 65°C overnight. The reaction mixture was concentrated and the residue was purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to give compound 56-a (150 mg, 95%). Synthesis of compound 56 56-a (150 mg, 0.16 mmol), DMF (3 mL) and cesium fluoride (243 mg, 1.60 mmol) were added to a reaction vial at room temperature. The mixture was stirred at room temperature for 3 hours. Filtered, the filtrate was purified by reversed-phase column (mobile phase: water (0.01 M NH4HCO3) / acetonitrile 10 / 0 to 1 / 9) to give compound 56 (69 mg, 69%). LC-MS (ESI): m / z 625.4 (M+H)+. Synthetic route of comparative compound 2´ Synthesis of compound 2´-c 2,4,7-Trichloro-8-fluoropyrido[4,3-d]pyrimidine (330 mg, 1.31 mmol) and DCM (20 mL) were added to a reaction vial at room temperature. After degassed and purged with nitrogen, the above mixture was cooled to -78°C in a dry ice-acetone bath and was added DIPEA (338 mg, 2.62 mmol) and piperidine (134 mg, 1.57 mmol). After addition, the mixture was naturally warmed to room temperature and stirred overnight. Water was added to the reaction mixture and the aqueous phase was extracted with DCM. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by column chromatography (mobile phase: PE / EA 10 / 0 to 6 / 4) to give compound 2´-c (320 mg, 81%). Synthesis of compound 2´-b At room temperature, to a reaction vial were added 2´-c (320 mg, 1.06 mmol), ((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methanol (338 mg, 2.12 mmol), 1,4-dioxane (10 mL) and DIPEA (549 mg, 4.25 mmol). After degassed and purged with nitrogen, the reaction mixture was stirred at 90°C overnight. The reaction mixture was concentrated and the residue was purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to give compound 2´-b (350 mg, 78%). LC-MS (ESI): m / z 424.4 (M+H)+. Synthesis of compound 2´-a To a sealed tube at room temperature was added 2´-b (50 mg, 0.12 mmol), ((6-fluoro-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylmethylsilyl)ethynyl)naphthalen-2- yl)oxy)triisopropylsilane (111 mg, 0.18 mmol), cataCXium A Pd G3 (9 mg, 0.01 mmol), potassium phosphate (75 mg, 0.35 mmol), THF (2 mL) and water (0.5 mL). After degassed and purged with nitrogen, the reaction mixture was stirred at 65°C overnight. The reaction mixture was concentrated and the residue was purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to afford compound 2´-a (67 mg, 64%). Synthesis of compound 2´ 2´-a (67 mg, 0.08 mmol), DMF (2 mL), and cesium fluoride (115 mg, 0.76 mmol) were added to a reaction vial at room temperature. After degassed and purged with nitrogen, the reaction mixture was stirred at 60 °C for 1 h. The reaction mixture was filtered and the filtrate was purified by prep- HPLC to give compound 2´ (29 mg, 67%). LC-MS (ESI): m / z 574.8 (M+H)+. Synthetic route of compound 57

[0020] Synthesis of compound 57-f Compound 3-[[tert-butyl(dimethyl)methylsilyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-7- yl]methanol (1.5 g, 0.0053 mol) was dissolved in 1,2-dichloroethane (10 mL), to which were added triethylamine (0.8 g, 0.0079 mol), 4-dimethylaminopyridine (60 mg, 0.49 mmol) and triphenylchloromethane (1.6 g, 0.0058 mol). After degassed and purged with nitrogen, the reaction mixture was stirred at 65°C for 2 hours. The reaction mixture was added water (100 mL), extracted with ethyl acetate (100 mL). The organic phase was washed with brine (50 mL), dried over sodium sulfate, filtered off the desiccant, and the filtrate was concentrated at reduced pressure to obtain the crude product, which was purified by column chromatography (mobile phase, PE / EA 3 / 1) to obtain the compound 57-f (2.6 g, 94%). LC-MS (ESI): m / z 528.2 (M+H)+. Synthesis of compound 57-e Compound 57-f (2.6 g, 4.93 mmol) was dissolved in tetrahydrofuran (10 mL), to which was added a solution of tetrabutylammonium fluoride (1M, 19.7 mL, 19.7 mmol) in tetrahydrofuran, and the mixture was stirred for 2 h at 50 °C. Water (100 mL) was added to the reaction mixture and the aqueous phase was extracted with ethyl acetate (150 mL). The organic phase was washed for four times with water (100 mL), brine (50 mL), dried over sodium sulfate, filtered off the desiccant, and the filtrate was concentrated at reduced pressure to obtain the crude product, which was purified by column chromatography (mobile phase, DCM / MeOH 10 / 1) to give compound 57-e (1.06 g.52%). LC-MS (ESI): m / z 414.5 (M+H)+. Synthesis of compound 57-d Compound 57-e (1.06 g, 2.56 mmol) was dissolved in tetrahydrofuran (5 mL), followed by addition of sodium tert-butanol (430 mg, 3.83 mmol) and the mixture was stirred for 30 min, then cooled in an ice-water bath, it was added 3-chloro-5-(trifluoromethyl)pyrazine (560 mg, 3.07 mmol), and the mixture was stirred for 1 h at room temperature. To the reaction mixture was added saturated ammonium chloride solution (1 mL) and water (50 mL) and the aqueous phase was extracted with ethyl acetate (50 mL). The organic phase was washed with brine (50 mL), dried over sodium sulfate, filtered off the desiccant, and the filtrate was concentrated at reduced pressure to obtain the crude product, which was dissolved in ethyl acetate (4 mL), to which was added hydrochloride / 1,4- dioxane (4M, 1 mL), the reaction mixture was stirred for 1 hr at room temperature, and then the reaction mixture was concentrated at reduced pressure, and then neutralized by the addition of 7M ammonia methanol solution and concentrated to obtain the crude product, which was purified by column chromatography (mobile phase, DCM / MeOH 10 / 1) to obtain compound 57-d (520 mg, 64%). LC-MS (ESI): m / z 318.1 (M+H)+. Synthesis of compound 57-c Compound 3-c (614 mg, 1.47 mmol) and 57-d (520 mg, 1.64 mmol) were dissolved in dichloromethane (10 mL). In an ice-water bath, the mixture was added sodium tert-butanol (236 mg, 2.46 mmol) and stirred for 2 hr in an ice-water bath. To the reaction mixture saturated ammonium chloride solution was added to neutralize, water (100 mL) was added and the aqueous phase was extracted with dichloromethane (100 mL). The organic phase was washed with brine (100 mL), dried over sodium sulfate, filtered off the desiccant, and the filtrate was concentrated at reduced pressure to obtain the crude product, which was purified by column chromatography (mobile phase, DCM / MeOH 20 / 1) to give compound 57-c (565 mg, 55%). LC-MS (ESI): m / z 697.4 (M+H)+. Synthesis of compound 57-b In a microwave tube, compound 57-c (150 mg, 0.22 mmol) and 7-fluoro-8- [(triisopropylsilyl)ethynyl]naphthalene-1-boronic acid pinacol ester (102 mg, 0.23 mmol) were dissloved in tetrahydrofuran (4 mL) and water (1 mL), followed by addition of methanesulfonate [n-butylbis(1-adamantyl)phosphine] (2-amino-1,1'- biphenyl-2-yl)palladium(II) (16 mg, 0.021 mmol) and anhydrous potassium phosphate (183 mg, 0.86 mmol), and the reaction mixture was blown with nitrogen for 1 min and stirred for 12 h at 65 °C. Water (50 mL) was added to the reaction mixture and the aqueous phase was extracted with ethyl acetate (50 mL). The organic phase was washed with brine (50 mL), dried over sodium sulfate, filtered off the desiccant, and the filtrate was concentrated at reduced pressure to obtain the crude product, which was purified by column chromatography (mobile phase, DCM / MeOH 20 / 1) to give compound 57-b (200 mg, 94%). LC-MS (ESI): m / z 988.0 (M+H)+. Synthesis of compound 57-a Compound 57-b (200 mg, 0.20 mmol) was dissolved in N,N-dimethylformamide (5 mL), to which cesium fluoride (308 mg, 2.03 mmol) was added, and the reaction mixture was stirred for 1 h at room temperature. Water (100 mL) was added to the reaction mixture and the aqueous phase was extracted with ethyl acetate (50 mL). The organic phase was washed with brine (50 mL), dried over sodium sulfate, filtered off the desiccant, and the filtrate was concentrated at reduced pressure to obtain the crude product, which was purified by column chromatography (mobile phase, DCM / MeOH 20 / 1) to give compound 57-a (125 mg, 74%). LC-MS (ESI): m / z 831.6 (M+H)+. Synthesis of compound 57 Compound 57-a (120 mg, 0.14 mmol) was dissolved in acetonitrile (3 mL), to which hydrochloride / 1,4-dioxane (4 M, 0.3 mL) was added, and the reaction mixture was stirred for 12 h at room temperature. The reaction mixture was neutralized by adding saturated sodium bicarbonate solution and the aqueous phase was extracted with ethyl acetate (50 mL). The organic phase was washed with brine (50 mL), dried over sodium sulfate, filtered off the desiccant, and the filtrate was concentrated at reduced pressure to obtain the crude product, which was purified by prep-HPLC (basic conditions) to give compound 57 (32 mg, 30%). LC-MS (ESI): m / z 731.0(M+H)+. Synthetic route of compound 58 Synthesis of compound 58-b In a microwave tube, compound 57-c (177 mg, 0.25 mmol) and 7-fluoro-8- [(triisopropylsilyl)ethynyl]-3-[(triisopropylsilyl)oxy]-1-naphthalenyl]boronic acid pinacol ester (175 mg, 0.28 mmol) were dissloved in tetrahydrofuran (4 mL) and water (1 mL), followed by addition of methanesulfonated[butylbis(1-adamantyl)phosphine] (2-amino-1,1'-biphenyl-2- yl)palladium(II) (37 mg, 0.051 mmol) and anhydrous potassium phosphate (216 mg, 1.02 mmol), and the reaction mixture was purged with nitrogen for 1 minute and stirred at 65 °C for 12 hours. Water (50 mL) was added to the reaction mixture and the aqueous phase was extracted with ethyl acetate (50 mL). The organic phase was washed with brine (50 mL), dried over sodium sulfate, filtered off the desiccant, and the filtrate was concentrated at reduced pressure to obtain the crude product, which was purified by column chromatography (mobile phase, DCM / MeOH 20 / 1) to give compound 58-b (260 mg, 88%). Synthesis of compound 58-a Compound 58-b (260 mg, 0.22 mmol) was dissolved in N,N-dimethylformamide (5 mL), to which cesium fluoride (341 mg, 2.24 mmol) was added, and the reaction mixture was stirred at room temperature for 4 hours. Water (100 mL) was added to the reaction mixture and the aqueous phase was extracted with ethyl acetate (100 mL). The organic phase was washed with brine (100 mL), dried over sodium sulfate, filtered off the desiccant, and the filtrate was concentrated at reduced pressure to obtain the crude product, which was purified by column chromatography (mobile phase, DCM / MeOH 20 / 1) to give compound 58-a (150 mg, 79%). LC-MS (ESI): m / z 847.2 (M+H)+. Synthesis of compound 58 Compound 58-a (150 mg, 0.18 mmol) was dissolved in acetonitrile (3 mL), to which hydrochloride / 1,4-dioxane (4 M, 0.3 mL) was added, and the reaction mixture was stirred for 12 h at room temperature. The reaction mixture was neutralized by adding saturated sodium bicarbonate solution and the aqueous phase was extracted with ethyl acetate (50 mL). The organic phase was washed with brine (50 mL), dried over sodium sulfate, filtered off the desiccant, and the filtrate was concentrated at reduced pressure to obtain the crude product, which was purified by prep-HPLC (basic conditions) to give compound 58 (50 mg, 38%). LC-MS (ESI): m / z 747.6(M+H)+;1H NMR (400MHz, DMSO-d6): δ 10.23(1H, s), 10.13(1H, s), 9.30(1H, s),8.00-7.94(1H, m), 7.74(1H, s), 7.49-7.42(1H, m), 7.38(1H, s), 7.19-7.16(1H, m), 5.88-5.83(1H, m), 4.48-4.35(2H, m), 4.16- 4.90(4H, m), 3.94-3.90(1H, m), 3.21-3.12(1H, m), 3.08-2.95(3H, m), 2.81-2.73(1H, m), 2.15- 2.02(2H, m), 1.95-1.60(12H, m). Synthetic route of compound 59 Synthesis of compound 59-d Compound 57-e (310 mg, 0.75 mmol) was dissolved in tetrahydrofuran (10 mL), to which potassium tert-butanolate (126 mg, 1.12 mmol) was added and the resulting mixture was stirred for 30 min. Then placed in an ice-water bath, the mixture was added 4-chloro-6-trifluoromethylpyrimidine (164 mg, 0.90 mmol), and was stirred for 2 h at room temperature. Water (50 mL) was added to the reaction mixture and the aqueous phase was extracted with ethyl acetate (50 mL). The organic phase was washed with brine (50 mL), dried over sodium sulfate, filtered off the desiccant and the filtrate was concentrated at reduced pressure to obtain the crude product. The crude product was dissolved in ethyl acetate (2 mL), to which hydrochloride / 1,4-dioxane (4M, 0.5 mL) was added, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated at reduced pressure, to which 7M ammonia methanol solution was added to neutralize and concentrate to obtain the crude product, which was purified by column chromatography (mobile phase, DCM / MeOH 10 / 1) to obtain the compound 59-d (228 mg, 96%). LC-MS (ESI): m / z 318.3 (M+H)+. Synthesis of compound 59-c Compounds 3-c (299 mg, 0.72 mmol) and 59-d (228 mg, 0.72 mmol) were dissolved in dichloromethane (10 mL). In an ice-water bath, the above mixture was added sodium tert-butoxide (173 mg, 1.80 mmol) and the reaction mixture was stirred for 3 hr in an ice-water bath bath. The reaction mixture was neutralized by adding saturated ammonium chloride solution to the reaction mixture, water (100 mL) was added and the aqueous phase was extracted with dichloromethane (50 mL). The organic phase was washed with brine (50 mL), dried over sodium sulfate, filtered off the desiccant, and the filtrate was concentrated at reduced pressure to obtain the crude product, which was purified by column chromatography (mobile phase, DCM / MeOH 20 / 1) to obtain the compound 59-c (142 mg, 28%). LC-MS (ESI): m / z 697.4 (M+H)+. Synthesis of compound 59-b In a microwave tube, compound 59-c (140 mg, 0.20 mmol) and 7-fluoro-8- [(triisopropylsilyl)ethynyl]naphthalene-1-boronic acid pinacol ester (136 mg, 0.30 mmol) were dissolved in tetrahydrofuran (4 mL) and water (1 mL), followed by addition of methanesulfonated [n-butylbis(1-adamantyl)phosphine] (2-amino-1,1'- biphenyl-2-yl)palladium(II) (29 mg, 0.040 mmol), anhydrous potassium phosphate (171 mg, 0.81 mmol), and the reaction mixture was blown with nitrogen for 1 min and stirred for 12 h at 65 °C. Water (50 mL) was added to the reaction mixture and the aqueous phase was extracted with ethyl acetate (50 mL). The organic phase was washed with brine (50 mL), dried over sodium sulfate, filtered off the desiccant, and the filtrate was concentrated at reduced pressure to obtain the crude product, which was purified by column chromatography (mobile phase, DCM / MeOH 20 / 1) to give compound the compound 59-b (110 mg, 56%). LC-MS (ESI): m / z 988.1(M+H)+. Synthesis of compound 59-a Compound 59-b (140 mg, 0.14 mmol) was dissolved in N,N-dimethylformamide (5 mL), to which cesium fluoride (215 mg, 1.42 mmol) was added, and the reaction mixture was stirred for 2 h at room temperature. Water (100 mL) was added to the reaction mixture and the aqueous phase was extracted with ethyl acetate (50 mL). The organic phase was washed with brine (50 mL), dried over sodium sulfate, filtered off the desiccant, and the filtrate was concentrated at reduced pressure to obtain the crude product, which was purified by column chromatography (mobile phase, DCM / MeOH 20 / 1) to give compound 59-a (100 mg, 85%). LC-MS (ESI): m / z 831.8 (M+H)+. Synthesis of compound 59 Compound 59-a (100 mg, 0.12 mmol) was dissolved in acetonitrile (2 mL), to which hydrochloride / 1,4-dioxane (4 M, 0.2 mL) was added, and the reaction mixture was stirred for 12 h at room temperature. The reaction mixture was neutralized with saturated sodium bicarbonate solution and the aqueous phase was extracted with ethyl acetate (50 mL). The organic phase was washed with brine (50 mL), dried over sodium sulfate, filtered off the desiccant, and the filtrate was concentrated at reduced pressure to obtain the crude product, which was purified by prep-HPLC (basic conditions) to give compound 59 (50 mg, 57%). LC-MS (ESI): m / z 731.0(M+H)+. Synthetic route of compound 60 Synthesis of compound 60-b In a microwave tube, compound 59-c (190 mg, 0.27 mmol) and 7-fluoro-8- [(triisopropylsilyl)ethynyl]-3-[(triisopropylsilyl)oxy]-1-naphthalenyl]boronic acid pinacol ester (255 mg, 0.41 mmol) were dissloved in tetrahydrofuran (4 mL) and water (1 mL), followed by addition of methanesulfonated [butylbis(1-adamantyl)phosphine] (2-amino-1,1'-biphenyl-2- yl)palladium(II) (40 mg, 0.055 mmol), and anhydrous potassium phosphate (231 mg, 1.09 mmol), and the reaction mixture was purged with nitrogen for 1 min, and stirred for 12 hr at 65 °C. Water (50 mL) was added to the reaction mixture and the aqueous phase was extracted with ethyl acetate (50 mL). The organic phase was washed with brine (50 mL), dried over sodium sulfate, filtered off the desiccant, and the filtrate was concentrated at reduced pressure to obtain the crude product, which was purified by column chromatography (mobile phase, DCM / MeOH 20 / 1) to give compound 60-b (200 mg, 63%). LC-MS (ESI): m / z 1159.9 (M+H)+. Synthesis of compound 60-a Compound 60-b (200 mg, 0.17 mmol) was dissolved in N,N-dimethylformamide (5 mL), to which cesium fluoride (362 mg, 1.72 mmol) was added, and the reaction mixture was stirred at room temperature for 4 hours. Water (100 mL) was added to the reaction mixture and the aqueous phase was extracted with ethyl acetate (100 mL). The organic phase was washed with brine (100 mL), dried over sodium sulfate, filtered off the desiccant, and the filtrate was concentrated at reduced pressure to obtain the crude product, which was purified by column chromatography (mobile phase, DCM / MeOH 20 / 1) to give compound 60-a (120 mg, 82%). LC-MS (ESI): m / z 847.7 (M+H)+. Synthesis of compound 60 Compound 60-a (120 mg, 0.14 mmol) was dissolved in acetonitrile (4 mL), to which hydrochloride / 1,4-dioxane (4 M, 0.4 mL) was added, and the reaction mixture was stirred for 12 h at room temperature. The reaction mixture was neutralized with saturated sodium bicarbonate solution and the aqueous phase was extracted with ethyl acetate (50 mL). The organic phase was washed with brine (50 mL), dried over sodium sulfate, filtered off the desiccant, and the filtrate was concentrated at reduced pressure to obtain the crude product, which was purified by prep-HPLC (basic conditions) to give compound 60 (50 mg, 47%). LC-MS (ESI): m / z 747.3(M+H)+. Synthetic route of compound 61 Synthesis of compound 61-d Compound 40-c (200 mg, 0.31 mmol) was dissolved in acetonitrile (10 mL), to which hydrochloride / 1,4-dioxane (4 M, 1 mL) was added in an ice-water bath, and the reaction mixture was stirred in an ice-water bath for 2 hours. Saturated sodium bicarbonate solution was added to the reaction mixture to neutralize, water (10 mL) and the aqueous phase was extracted with ethyl acetate (50 mL). The organic phase was washed with brine (50 mL), dried over sodium sulfate, filtered off the desiccant, and the filtrate was concentrated at reduced pressure to obtain the crude product, which was purified by column chromatography (mobile phase, DCM / 7M ammonia-methanol 10 / 1) to give compound 61-d (110 mg, 65%). LC-MS (ESI): m / z 540.3 (M+H)+. Synthesis of compound 61-c Compound 61-d (110 mg, 0.21 mmol) and acetic anhydride (31 mg, 0.30 mmol) were dissolved in dichloromethane (3 mL), followed by addition of 4-dimethylaminopyridine (37 mg, 0.30 mmol), and the mixture was stirred for 1 hour at room temperature. Water (50 mL) was added to it and the aqueous phase was extracted with dichloromethane (50 mL). The organic phase was washed with brine (50 mL), dried over sodium sulfate, filtered off the desiccant, and the filtrate was concentrated at reduced pressure to obtain the crude product, which was purified by column chromatography (mobile phase, DCM / MeOH 20 / 1) to give compound 61-c (110 mg, 93%). LC-MS (ESI): m / z 582.6 (M+H)+. Synthesis of compound 61-b In a microwave tube, compound 61-c (110 mg, 0.19 mmol) and pinacol ester of 7-fluoro-8- [(triisopropylsilyl)ethynyl]-3-[(triisopropylsilyl)oxy]-1-naphthalenyl]boronic acid (130 mg, 0.21 mmol) were dissloved in tetrahydrofuran (4 mL) with water (1 mL), followed by addition of methanesulfonated [butylbis(1-adamantyl) alkyl)phosphine](2-amino-1,1 '-biphenyl-2- yl)palladium(II) (28 mg, 0.038 mmol) and anhydrous potassium phosphate (160 mg, 0.75 mmol), and the reaction mixture was purged with nitrogen for 1 min, and stirred for 12 h at 65 °C. The reaction mixture was added water (50 mL), extracted with ethyl acetate (50 mL), washed with brine (50 mL), dried over sodium sulfate, filtered off the desiccant, and the filtrate was concentrated at reduced pressure to obtain the crude product, which was purified by column chromatography (mobile phase, DCM / MeOH 20 / 1) to obtain compound 61-b (130 mg, 77%). LC-MS (ESI): m / z 888.8(M+H)+. Synthesis of compound 61-a Compound 61-b (130 mg, 0.15 mmol) was dissolved in N,N-dimethylformamide (5 mL), to which cesium fluoride (222 mg, 1.46 mmol) was added, and the reaction mixture was stirred for 4 h at room temperature. Water (100 mL) was added to the reaction mixture and the aqueous phase was extracted with ethyl acetate (50 mL). The organic phase was washed with brine (50 mL), dried over sodium sulfate, filtered off the desiccant, and the filtrate was concentrated at reduced pressure to obtain the crude product, which was purified by column chromatography (mobile phase, DCM / MeOH 20 / 1) to obtain compound 61-a (90 mg, 84%). LC-MS (ESI): m / z 732.3 (M+H)+. Synthesis of compound 61 Compound 61-a (90 mg, 0.12 mmol) was dissolved in dichloromethane (2 mL), to which tert- butyldimethylsilyl trifluoromethanesulfonate (33 mg, 0.12 mmol) was added, and the reaction mixture was stirred for 5 h at room temperature. Saturated sodium bicarbonate solution (10 mL) was added to the reaction mixture and continued stirring for 1 h. The reaction mixture was extracted with dichloromethane (50 mL). The organic phase was washed with brine (50 mL), dried over sodium sulfate, filtered off the desiccant, and the filtrate was concentrated at reduced pressure to obtain the crude product, which was purified by prep-HPLC (basic conditions) to give compound 61 (12 mg, 16%). LC-MS (ESI): m / z 632.3 (M+H)+. Synthetic route of compound 62 Synthesis of compound 62-a Compound 40-b-2 (140 mg, 0.15 mmol) was dissolved in N,N-dimethylformamide (4 mL), to which cesium fluoride (225 mg, 1.48 mmol) was added, and the reaction mixture was stirred at room temperature for 4 hours. Water (100 mL) was added to the reaction mixture and the aqueous phase was extracted with ethyl acetate (100 mL). The organic phase was washed with brine (100 mL), dried over sodium sulfate, filtered off the desiccant, and the filtrate was concentrated at reduced pressure to obtain the crude product, which was purified by column chromatography (mobile phase, DCM / MeOH 20 / 1) to obtain the intermediate product, which was dissolved in acetonitrile (3 mL), followed by addition of hydrochloride / 1,4-dioxane (4M, 0.3 mL) in an ice-water bath, then stirred for 2 h. The reaction mixture was neutralized with saturated sodium bicarbonate solution and the aqueous phase was extracted with ethyl acetate (100 mL). The organic phase was washed with brine (100 mL), dried over sodium sulfate, filtered off the desiccant, and the filtrate was concentrated at reduced pressure to give compound 62-a (80 mg, 78%). LC-MS (ESI): m / z 690.5 (M+H)+. Synthesis of compound 62 Compound 62-a (80 mg, 0.12 mmol) was dissolved in dichloromethane (4 mL), followed by addition of diisopropylethylamine (30 mg, 0.23 mmol) and acryloyl chloride (13 mg, 0.14 mmol) and the reaction mixture was stirred for 1 h at room temperature. Water (50 mL) was added to the reaction mixture and the aqueous phase was extracted with dichloromethane (50 mL). The organic phase was washed with brine (50 mL), dried over sodium sulfate, filtered off the desiccant, and the filtrate was concentrated at reduced pressure to obtain the crude product, which was purified by column chromatography (mobile phase, DCM / MeOH 20 / 1) to obtain the intermediate product, which was dissolved in formic acid (2 mL), and the reaction mixture was stirred for 36 hours at room temperature. The reaction mixture was concentrated at reduced pressure to obtain the crude product, which was purified by prep-HPLC (basic conditions) to give compound 62 (17 mg, 23%). LC-MS (ESI): m / z 644.3 (M+H)+. Synthetic route of compound 63 Synthesis of compound 63-a Compound 12 (100 mg, 0.15 mmol) was dissolved in 20 mL of dichloromethane at room temperature, TEA (40 uL, 0.29 mmol) was added, palmitoyl chloride (120 mg, 0.44 mmol) was added to the reaction mixture in an ice-water bath, and the reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was added 1 mL of methanol and stirred for 20 minutes. The reaction mixture was concentrated at reduced pressure and the residue was purified by a flash column chromatography (DCM / MeOH=20:1) to give the crude compound 63-a (134 mg). LC-MS (ESI): m / z = 927.3 [M+H]+. Synthesis of compound 63 Compound 63-a (134 mg, 0.14 mmol) was dissolved in 5 mL of DCM at room temperature and tert- butyldimethylsilyl trifluoromethanesulfonate (270 uL, 1.18 mmol) was added to the reaction mixture in an ice-water bath and the reaction mixture was stirred for 1 hour in an ice-water bath. The reaction mixture was added 10% sodium bisulfate solution (10 mL) at room temperature and stirred for 30 min, then saturated sodium bicarbonate solution was added and the pH was adjusted to basic, extracted with DCM (50 mL*2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated at reduced pressure, and the residue was purified by a flash column chromatography (DCM / MeOH=10:1) to give compound 63 (50 mg, 43%). LC- MS (ESI): m / z = 827.4 [M+H]+. Synthetic route of compound 64 Synthesis of compound 64-c At room temperature, compound 6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5- ((triisopropylsilyl)ethynyl)naphthalene-2-phenol (400 mg, 0.85 mmol) was dissolved in 20 mL of anhydrous acetonitrile, followed by addition of SelectFluor II (1-fluoro-4-methyl-1,4-diaza bicyclo[2.2.2]octane tetrafluoroborate) (410 mg, 1.28 mmol), and the reaction mixture was stirred at 80oC under protection of nitrogen for 2 hours. The reaction mixture was cooled to room temperature, concentrated at reduced pressure and the residue was purified by flash column chromatography (PE / EA=3:1) to afford compound 64-c (145 mg, 35%). LC-MS (ESI): m / z = 487.3 [M+H]+. Synthesis of compound 64-b At room temperature, 3-b (80 mg, 0.15 mmol), 64-c (79 mg, 0.16 mmol), methylsulfonyloxy(diadamantyl-n-butylphosphino)-2′-amino-1,1'-biphenyl-2-yl)palladium(II) (22 mg, 0.03 mmol), potassium phosphate (95 mg , 0.45 mmol), THF (2.5 mL), and water (0.5 mL) were combined in a microwave tube. After degassed and purged with nitrogen 3 times, the reaction mixture was stirred at 60oC for 18 hours. The reaction mixture was cooled to room temperature, concentrated at reduced pressure, and the residue was purified by flash column chromatography (DCM / MeOH = 20:1) to afford compound 64-b (66 mg, 51%). LC-MS (ESI): m / z = 863.4 [M+H]+. Synthesis of compound 64-a Compound 64-b (66 mg, 0.076 mmol) was dissolved in 3 mL of DMF at room temperature, cesium fluoride (209 mg, 1.38 mmol) was added, and the mixture was stirred at room temperature under protection of nitrogen for 2 hours. The reaction mixture was added 20 mL of water, and the aqueous phase was extracted with ethyl acetate (50 mL*2). The organic phase was washed with brine (100 mL*5), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated at reduced pressure to give the crude compound 64-a (47 mg, 87%). LC-MS (ESI): m / z = 707.3 [M+H]+. Synthesis of compound 64 Compound 64-a (47 mg, 0.067 mmol) was dissolved in 6 mL of dichloromethane at room temperature, tert-butyldimethylsilyl trifluoromethanesulfonate (200 uL, 0.87 mmol) was added in an ice-water bath, and the reaction mixture was stirred in an ice-water bath for 30 min. The reaction mixture was added 50 mL of saturated sodium bicarbonate solution, diluted with 30 mL of dichloromethane, and stirred at room temperature for 6 hours. The reaction mixture was extracted with dichloromethane (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated at reduced pressure to give compound the crude product, which was purified by prep-HPLC (basic method, NH4HCO3) to give compound 64 (10.8 mg, 26%). LC-MS(ESI): m / z= 607.3[M+H]+. Synthetic route of compound 65 Synthesis of compound 65 Compound 4 (50 mg, 0.085 mmol) was dissolved in 5 mL of dichloromethane at room temperature, NCS (N-chlorosuccinimide) (17 mg, 0.13 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated at reduced pressure and the residue was purified by flash column chromatography (DCM / MeOH=10:1) to obtain the crude product, which was further purified by prep-HPLC (basic method, NH4HCO3system) to give compound 65 (3 mg, 5.7%). LC-MS (ESI): m / z = 623.2 [M+H]+. Synthetic route of compound 66 Synthesis of compound 66-a To a microwave tube were added 3-b (100 mg, 0.19 mmol), 2-(7,8-difluoro-3- (methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (97 mg, 0.28 mmol), potassium phosphate (118 mg, 0.56 mmol), cataCXium A Pd G3 ( 14 mg, 0.019 mmol), tetrahydrofuran (10 mL), water (1 mL). After degassed and purged with nitrogen for three times, the microwave tube was sealed and stirred at 65oC overnight. The reaction mixture was concentrated to dryness and the residue was purified by column chromatography (mobile phase: methanol: dichloromethane = 0-5%) to give compound 66-a (107 mg, 79%). Synthesis of compound 66 Formic acid (4 mL) was combined with 66-a (30 mg, 0.041 mmol) at room temperature and the mixture was stirred at 35oC overnight. The reaction mixture was concentrated to dryness, purified by prep-HPLC (ammonium bicarbonate) and lyophilized to give compound 66 (9 mg, 37%). LC- MS (ESI): m / z 583.3 (M+H)+. Synthetic route of compound 67 Synthesis of compound 67-f A reaction vial charged with tert-butyl carbazate (2 g, 15.13 mmol), ethanol (80 mL) and methyl 5- oxovalerate (1.97 g, 15.14 mmol) was stirred at room temperature overnight under atmosphere of nitrogen. After addition of 10% Pd / C (1.6 g, 1.51 mmol), the mixture was degassed and purged with hydrogen for three times and stirred at room temperature overnight. The reaction mixture was filtered through celite, the filtrate was concentrated to dryness and the residue was purified by column chromatography (mobile phase ethyl acetate: petroleum ether = 0-50%) to give compound 67-f (1.35 g, 36%). LC-MS (ESI): m / z 247.2 (M+H)+. Synthesis of compound 67-e A reaction vial charged with 67-f (300 mg, 1.22 mmol), dichloromethane (40 mL) was added 2,4,7- trichloro-8-fluoropyrido[4,3-d]pyrimidine (307 mg, 1.22 mmol) while cooled in a dry ice-acetone bath and stirred for 2 hr at room temperature under atmosphere of nitrogen. The reaction mixture was concentrated to dryness and the residue was purified by column chromatography (mobile phase: ethyl acetate: petroleum ether = 0-30%) to give compound 67-e (293 mg, 52%). LC-MS (ESI): m / z 462.1 (M+H)+. Synthesis of compound 67-d A reaction vial charged with 67-e (293 mg, 0.63 mmol), ((2R,7aS)-2-fluorohexahydro-1H- pyrrolizin-7a-yl)methanol (303 mg, 1.90 mmol), 1,4-dioxane (20 mL) and DIPEA (410 mg, 3.17 mmol) was degassed and purged with nitrogen for three times, then stirred at 90oC for three days. The reaction mixture was concentrated to dryness and the residue was purified by column chromatography (mobile phase: methanol: dichloromethane = 0-5%) to give compound 67-d (348 mg, 94%). LC-MS (ESI): m / z 585.3 (M+H)+. Synthesis of compound 67-c A reaction vial charged with 67-d (348 mg, 0.595 mmol), acetonitrile (20 mL), hydrochloride / 1,4- dioxane(4M, 2 mL, 8 mmol) was stirred at room temperature overnight. The reaction mixture was concentrated to dryness to give compound 67-c (crude), which was used directly in the next step without purification. LC-MS (ESI): m / z 485.3 (M+H)+. Synthesis of compound 67-b A reaction vial charged with 67-c (crude, 0.59 mmol), methanol (10 mL), tetrahydrofuran (32 mL), water (3 mL) and lithium hydroxide (249 mg, 5.94 mmol) was stirred at room temperature for 2 hours. The reaction mixture was adjusted to pH 4 with 1 M hydrochloric acid, removed the water by rotary evaporation, removed the water twice with ethanol and twice with acetonitrile. The residue was add acetonitrile (100 mL), HOBt (401 mg, 2.97 mmol), EDCI (683 mg, 3.56 mmol) and DIPEA (0.982 mL, 5.94 mmol), then stirred at room temperature overnight under atmosphere of nitrogen. Supplemented with HOBt (401 mg, 2.97 mmol), EDCI (683 mg, 3.56 mmol), DIPEA (0.982 mL, 5.94 mmol), stirred at room temperature overnight under atmosphere of nitrogen. Acetonitrile was removed by rotary evaporation and water was added, the aqueous phase was extracted with ethyl acetate (80 mL*2). The organic phase was washed with brine, dried over anhydrous sodium sulfate, concentrated to dryness, and the residue was purified by column chromatography (mobile phase: methanol: dichloromethane = 0-10%) to give compound 67-b (40 mg, 15%). LC-MS (ESI): m / z 453.2(M+H)+. Synthesis of compound 67-a To a microwave tube were added 67-b (40 mg, 0.088 mmol), ((6-fluoro-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-5-((triisopropylmethylsilyl)ethynyl)naphthalen-2- yl)oxy)triisopropylsilane (83 mg, 0.13 mmol), potassium phosphate (94 mg, 0.44 mmol), cataCXium A Pd G3 (6 mg, 0.009 mmol), tetrahydrofuran (10 mL) and water (1 mL). After sealed, degassed and purged with nitrogen for three times, the microwave tube was stirred at 65oC overnight. The reaction mixture was concentrated to dryness and the residue was purified by column chromatography (mobile phase: methanol: dichloromethane = 0-10%) to give compound 67-a (40 mg, 49%). LC-MS (ESI): m / z 915.4 (M+H)+. Synthesis of compound 67 To 67-a (40 mg, 0.044 mmol) were added DMF (3 mL) and cesium fluoride (66 mg, 0.44 mmol) at room temperature and the mixture was stirred at room temperature overnight. The reaction mixture was filtered, and the filtrate was purified by prep-HPLC (ammonium bicarbonate) and immediately lyophilized to give compound 67 (6 mg, 23%). LC-MS (ESI): m / z 603.3 (M+H)+. Synthetic route of compound 68 Synthesis of compound 68 To a solution of compound 4 (125 mg, 0.21 mmol) in dichloromethane (10 mL) in an ice-water bath was added triethylamine (64 mg, 0.63 mmol), followed by slow addition of trifluoroacetic anhydride (66 mg, 0.32 mmol). The mixture was warmed to room temperature and stirred for 2 hours. Upon completion of the reaction, the organic solvent was removed by concentration under low temperature at reduced pressure. The crude was purified by flash column chromatography (mobile phase: methanol / dichloromethane, 0-10%) to give compound 68 (75 mg, 52%). LC-MS (ESI): m / z 685.7 [M+H]+;1H NMR (DMSO-d6, 400 MHz): δ 10.19 (1H, d, J = 7.2 Hz), 8.67 (1H, s), 7.95- 8.04 (1H, m), 7.44-7.52 (1H, m), 7.41 (1H, s), 7.16-7.28 (1H, m), 5.30 (1H, d, J = 54.4 Hz), 4.04- 4.66 (4H, m), 3.51-3.98 (3H, m), 2.96-3.23 (3H, m), 2.77-2.93 (1H, m), 1.50-2.29 (12H, m). Synthetic route of compound 69 Synthesis of compound 69 To a solution of compound 4 (180 mg, 0.31 mmol) in dichloromethane (50 mL) in an ice-water bath was added pyridine (242 mg, 3.06 mmol), followed by slow addition of n-octyl isocyanate (66 mg, 0.32 mmol). The mixture was warmed to room temperature and stirred for 3 hours. Upon completion, the reaction was removed organic solvent by concentration under low temperature and reduced pressure. The mixture was first purified by flash column chromatography (mobile phase: methanol / dichloromethane, 0-10%) to obtain the crude product, and then purified by prep-HPLC to obtain product 69 (60 mg, 26%). LC-MS (ESI): m / z 744.4 [M+H]+;1H NMR (400 MHz, CDCl3): δ 10.25 (1H, s), 7.60-7.90 (1H, m), 7.79 (1H, d, J = 2.0 Hz), 7.40-7.50 (1H, m), 7.31 (1H, t, J = 8.8 Hz), 5.30 (1H, d, J = 53.6 Hz), 5.12 (1H, t, J = 6.0 Hz), 4.01-4.39 (5H, m), 3.10-3.52 (7H, m), 2.95- 3.05 (1H, m), 2.86 (1H, m), 2.13-2.41 (3H, m), 1.85-2.09 (5H, m), 1.68-1.85 (5H, m), 1.52-1.64 (3H, m), 1.18-1.43 (8H, m), 0.82-0.94 (3H, m). Synthetic route of compounds 70 and 71

[0021] Synthesis of compound 70-b To a microwave tube were added compound 41-c (200 mg, 0.32 mmol), 6-fluoro-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-amine (227 mg, 0.49 mmol), palladium tetrakis(triphenylphosphine) (38 mg, 0.032 mmol), sodium carbonate (103 mg, 0.97 mmol), 1,4-dioxane (15 mL) and water (1.5 mL). After sealed, degassed and purged with nitrogen for three times, the microwave tube was stirred at 100 °C overnight. The reaction mixture was concentrated to dryness and the crude product was purified by column chromatography (mobile phase: methanol / dichloromethane, 0-10%) to give compound mixture 70-b (200 mg, 70%). LC-MS (ESI): m / z 877.1 (M+H)+; m / z 721.3 (M+H)+. Synthesis of compound 70-a To a solution of compound 70-b (200 mg, 0.23 mmol) in N,N-dimethylformamide (4 mL) was added cesium fluoride (346 mg, 2.28 mmol) at room temperature, and the mixture was stirred for 1 h at room temperature. A large amount of The reaction mixture was poured water and the aqueous phase was extracted with ethyl acetate (50 mL*2). The organic phase was washed with brine (30 mL*3), concentrated to dryness, and the residue was purified by column chromatography (mobile phase: methanol / dichloromethane, 0-10%) to give compound a mixture of the two isomers, 70-a (140 mg, 85%). LC-MS (ESI): m / z 721.6 (M+H)+. Synthesis of compounds 70 and 71 To a solution of compound 70-a (140 mg, 0.19 mmol) in dichloromethane (4 mL) was added tert- butyldimethylsilyl trifluoromethanesulfonate (205 mg, 0.77 mmol) at room temperature, and the mixture was stirred for 1 h at room temperature. The reaction mixture was quenched by addition of saturated sodium bicarbonate solution (10 mL) and the mixture was stirred at room temperature overnight. Upon completion, the reaction mixture was extracted with dichloromethane (15 mL*2). The organic phase was washed with brine (10 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The crude was purified by prep-HPLC (basic method) and lyophilized to give compound two products. Compound 70 (30 mg, 25%), LC-MS (ESI): m / z 621.3 (M+H)+; Compound 71 (40 mg, 33%). LC-MS (ESI): m / z 621.3 (M+H)+. Synthetic route of compound 72 Synthesis of compound 72-c To a solution of compound 3-c (100 mg, 0.24 mmol) in dichloromethane (15 mL) was added (S)- (-)-1-methyl-2-pyrrolidinomethanol (55 mg, 0.48 mmol) and then sodium tert-butoxide (115 mg, 1.20 mmol) in an ice-water bath. After addition, the reaction mixture was slowly warmed to room temperature and stirred at room temperature overnight. Water was added to the reaction mixture and the aqueous phase was extracted with dichloromethane (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered. The organic phase was concentrated to dryness, and the crude product was purified by flash column chromatography (mobile phase: dichloromethane:methanol=10:1 / dichloromethane, 0-100%) to obtain 72-c (70 mg, 59%). LC-MS (ESI): m / z 495.4 (M+H)+. Synthesis of compound 72-b To a 10 mL microwave tube were added 72-c (70 mg, 0.14 mmol), ((6-fluoro-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylmethylsilyl)ethynyl)naphthalen-2- yl)oxy)triisopropylsilane (106 mg, 0.17 mmol), methanesulfonic acid [n-butylbis(1- adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (10 mg, 0.014 mmol), potassium phosphate (90 mg, 0.42 mmol), tetrahydrofuran (2.5 mL) and water (0.5 mL). The microwave tube was sealed. After degassed and purged with nitrogen several times, the reaction mixture was stirred at 65 °C overnight. Water was added to the reaction mixture and the aqueous phase was extracted with ethyl acetate (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness and the crude was purified by flash column chromatography (mobile phase Dichloromethane: methanol=10:1 / dichloromethane, 0-100%) to obtain 72-b (60 mg, 53%). LC-MS (ESI): m / z 801.7 (M+H)+. Synthesis of compound 72-a To a solution of 72-b (60 mg, 0.075 mmol) in N,N-dimethylformamide (8 mL) of was added cesium fluoride (95 mg, 0.63 mmol) at room temperature and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture and the aqueous phase was extracted with ethyl acetate (30 mL). The organic phase was washed twice with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to give compound 72-a (40 mg, 83%). LC-MS (ESI): m / z 645.5 (M+H)+. Synthesis of compound 72 Trifluoroacetic acid (2 mL) was added to a solution of 72-a (40 mg, 0.062 mmol) in dichloromethane (10 mL) at room temperature and the reaction mixture was stirred for 4 hours at this temperature. The reaction mixture was concentrated to dryness, neutralized by the addition of saturated aqueous sodium bicarbonate solution and the aqueous phase was extracted with dichloromethane (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness and the crude was purified by prep-HPLC to give compound 72 (3 mg, 9%). LC-MS (ESI): m / z 545.3 (M+H)+. Synthetic route of compound 73 Synthesis of compound 73-a To a solution of compound 12 (100 mg, 0.15 mmol) in N,N-dimethylformamide (6 mL) was added 1-chlorocarbonyl-4-piperidinylpiperidine hydrochloride (194 mg, 0.73 mmol) and potassium carbonate (201 mg, 1.45 mmol) at room temperature. The reaction mixture was stirred at 40 °C for 1 h. LCMS showed the reaction was complete, water was added to the reaction mixture and the aqueous phase was extracted with ethyl acetate (60 mL). The organic phase was washed twice with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to give compound 73-a (119 mg, 93%). The crude product was used directly in the next step without purification. LC-MS (ESI): m / z 883.8 (M+H)+. Synthesis of compound 73 To a solution of compound 73-a (119 mg, 0.13 mmol) in dichloromethane (10 mL) was added tert-butyldimethylsilyl trifluoromethanesulfonate (0.06 mL) in an ice-water bath, and the reaction mixture was stirred for 1 hr at this temperature, followed by the addition of saturated aqueous sodium bicarbonate and the reaction mixture was stirred at room temperature overnight. The reaction mixture was extracted with dichloromethane (30 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated to dryness and the crude was purified by prep-HPLC to give compound 73 (23 mg, 22%). LC-MS (ESI): m / z 783.4(M+H)+. Synthetic route of compound 74 Synthesis of compound 74 To a solution of compound 4 (100 mg, 0.17 mmol) in DCM (2 mL) was added triethylamine (0.047 mL, 0.340 mmol) and p-nitrophenyl chloroformate (34 mg, 0.17 mmol) in an ice-salt bath and under protection of nitrogen. The reaction mixture was stirred at this temperature for 10 min, then was added (S)-2-(methoxymethyl)pyrazolidine (20 mg, 0.17 mmol) and slowly warmed to room temperature and the reaction mixture was stirred at room temperature overnight. Water was added to the reaction mixture and the aqueous phase was extracted with dichloromethane (30 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness and the crude was purified by prep-HPLC to give compound 74 (81 mg, 65%). LC-MS (ESI): m / z 730.3 (M+H)+. Synthetic route of compound 75 Synthesis of compound 75 Triethylamine (0.047mL, 0.340mmol) and p-nitrophenyl chloroformate (34mg, 0.17mmol) were added to a solution of compound 4 (100mg, 0.17mmol) in DCM (2mL) under atmosphere of nitrogen in an ice-salt bath. The reaction mixture was stirred at this temperature for 10 min, then was added tert-Butyl 2-piperidinecarboxylate (31 mg, 0.17 mmol) and the reaction mixture was warmed to room temperature and stirred overnight. Water was added to the reaction mixture and the aqueous phase was extracted with dichloromethane (30 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness and the crude was purified by prep-HPLC to give compound 75 (73 mg, 54%). LC-MS (ESI): m / z 800.3 (M+H)+. Synthetic route of compound 76 Synthesis of compound 76-e At room temperature, to a reaction vial were added di-tert-butyl hydrazodicarboxylate (2000 mg, 8.61 mmol), DMF (60 mL), cis-1,4-dichloro-2-butene (1076 mg, 8.61 mmol) and cesium carbonate (8416 mg, 25.83 mmol). After degassed and purged with nitrogen, the reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered and the filtrate was added water and the aqueous phase was extracted with EA. The organic phases were combined, washed with water, brine, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by column chromatography (mobile phase: PE / EA 10 / 0 to 8 / 2) to give compound 76-e (2000 mg, 82%). LC-MS (ESI): m / z 302.2 (M+ NH4)+. Synthesis of compound 76-d 76-e (500 mg, 1.76 mmol), acetonitrile (20 mL) and HCl / 1,4-dioxane (1M, 5 mL) were added to a reaction vial at room temperature. The mixture was protected with N2and stirred for 3 hours at room temperature. The reaction mixture was concentrated at room temperature to give the crude compound 76-d (430 mg). Synthesis of compound 76-c At room temperature, to a reaction vial were added 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (533 mg, 2.11 mmol), DCM (15 mL) and crude compound 76-d (430 mg, 1.76 mmol). After degassed and purged with nitrogen and cooled to 0°C, the mixture was was added DIPEA (1136 mg, 8.79 mmol). The reaction mixture was naturally warmed to room temperature and stirred overnight. Water was added to the reaction mixture and the aqueous phase was extracted with DCM. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated and the residue was purified by column chromatography (mobile phase: PE / EA 10 / 0 to 8 / 2) to give compound 76-c (430 mg, 81%). Synthesis of compound 76-b At room temperature, to a reaction vial were added 76-c (430 mg, 1.43 mmol), ((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methanol (342 mg, 2.15 mmol), 1,4-dioxane (5 mL) and DIPEA (741 mg, 5.73 mmol). After degassed and purged with nitrogen, the reaction mixture was stirred at 90°C overnight. The reaction mixture was concentrated and the residue was purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to give compound 76-b (600 mg, 99%). LC-MS (ESI): m / z 423.3 (M+H)+. Synthesis of compound 76-a 76-b (150 mg, 0.35 mmol), ((6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5- ((triisopropylmethylsilyl)ethynyl)naphthalen-2-yl)oxy)triisopropylsilane (266 mg, 0.43 mmol), cataCXium A Pd G3 (52 mg, 0.07 mmol), potassium phosphate (226 mg, 1.07 mmol), THF (2 mL), and water (0.5 mL) were combined in a sealed tube. After degassed and purged with nitrogen, the reaction mixture was stirred at 65°C overnight. The reaction mixture was concentrated and the residue was purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to give compound 76-a (220 mg, 70%). Synthesis of compound 76 76-a (220 mg, 0.25 mmol), DMF (3 mL) and cesium fluoride (377 mg, 2.48 mmol) were added to a reaction vial at room temperature. The mixture was stirred at room temperature for 3 hours. Filtered, and the filtrate was purified by reversed-phase column (mobile phase: water (0.01 M NH4HCO3) / acetonitrile 10 / 0 to 1 / 9) to give compound 76 (50 mg, 35%). LC-MS (ESI): m / z 573.4 (M+H)+;1H NMR (400MHz, CD3OD): δ 10.46 (1H, s), 10.04(1H, s), 7.91-7.80 (2H, m), 7.43- 7.18(4H, m), 5.60-5.54 (1H, m), 5.30(1H, d, J =53.2Hz), 4.39-4.19(3H, m), 3.40(2H, t, J =6.0Hz), 3.33(1H, d, J =3.2Hz), 3.27-3.13 (3H, m), 3.09-2.96 (1H, m), 2.50-1.80 (7H, m). Synthetic route of compound 77 Synthesis of compound 77-f At room temperature, to a reaction flask were added 5-bromo-2-fluoro-1-methyl-3-nitrobenzene (2500 mg, 10.68 mmol), ethanol (80 mL), water (40 mL), iron powder (5965 mg, 106.83 mmol) and ammonium chloride (5714 mg, 106.83 mmol). After degassed and purged with nitrogen, the reaction mixture was stirred at 100 °C for 2 hours. The reaction mixture was concentrated to remove ethanol, water and EA were added. Filtered and the filtrate was extracted with EA. The organic phases were combined, washed with water, brine, dried over anhydrous sodium sulfate, concentrated and the residue was purified by column chromatography (mobile phase: PE / EA 10 / 0 to 8 / 2) to give compound 77-f (1900 mg, 87%). Synthesis of compound 77-e At room temperature, to a reaction vial were added 77-f (1900 mg, 9.31 mmol) and DMF (15 mL). After degassed and purged with nitrogen and cooled down to 0°C, the mixture was added NaH (60%, 1490 mg, 37.25 mmol), stirred for half an hour, was added 4-methoxybenzyl chloride (PMBCl) (4375 mg, 27.94 mmol). The reaction mixture was naturally warmed to room temperature for 3 hours. Water was added to the reaction mixture and the aqueous phase was extracted with EA. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by column chromatography (mobile phase: PE / EA 10 / 0 to 8 / 2) to give compound 77- e (3600 mg, 87%). Synthesis of compound 77-d At room temperature, to a reaction vial were added 77-e (3600 mg, 8.10 mmol), acetic acid (25 mL), and NIS (N-iodosuccinimide) (1823 mg, 8.10 mmol). After degassed and purged with nitrogen, the reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was concentrated, neutralized with aqueous sodium bicarbonate and the aqueous phase was extracted with EA. The organic phases were combined, washed with water, dried over anhydrous sodium sulfate, concentrated and the residue was purified by column chromatography (mobile phase: PE / EA 10 / 0 to 9 / 1) to give compound 77-d (1900 mg, 41%). Synthesis of compound 77-c At room temperature, to a reaction vial were added 77-d (1900 mg, 3.33 mmol), methyl fluorosulfonyl difluoroacetate (3200 mg, 16.66 mmol), DMAc (20 mL) and CuI (3173 mg, 16.66 mmol). After degassed and purged with nitrogen, the reaction mixture was stirred at 90 °C for 2 h. The reaction mixture was cooled to room temperature, water was added, the aqueous phase was extracted with EA. The organic phases were combined, dried, concentrated and the residue was purified by column chromatography (mobile phase: PE / EA 10 / 0 to 10 / 1) to give compound 77-c (1300 mg, 76%). LC-MS (ESI): m / z 512.1 (M+H)+. Synthesis of compound 77-b At room temperature, to a reaction vial were added 77-c (1300 mg, 2.54 mmol), pinacol bis(boronic acid) ester (1933 mg, 7.61 mmol), Pd(dppf)Cl2 (371 mg, 0.51 mmol), potassium acetate (996 mg, 10.15 mmol), 1,4-dioxane (10 mL). After degassed and purged with nitrogen, the reaction mixture was stirred at 100 °C for 3 hours. The reaction mixture was concentrated and the residue was purified by column chromatography (mobile phase: PE / EA 10 / 0 to 10 / 1) to give compound 77-b (1300 mg, 92%). LC-MS (ESI): m / z 560.3 (M+H)+. Synthesis of compound 77-a 77-b (1300 mg, 2.32 mmol), TFA (10 mL) were added to a reaction vial at room temperature. After degassed and purged with nitrogen, the reaction mixture was stirred for 3 h at room temperature. The reaction mixture was concentrated at room temperature, alkalized by addition of methanol solution of ammonia, concentrated, and the residue was purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to give compound 77-a (450 mg, 61%). Synthesis of compound 77 To a sealed tube at room temperature was added 77-a (200 mg, 0.63 mmol), 20-d (330 mg, 0.75 mmol), cataCXium A Pd G3 (46 mg, 0.06 mmol), potassium phosphate (399 mg, 1.88 mmol), THF (4 mL) and water (1 mL). After degassed and purged with nitrogen, the reaction mixture was stirred at 65°C for 3 hours. The reaction mixture was concentrated, dissolved by adding methanol, filtered and the filtrate was purified by prep-HPLC to give compound 77 (56 mg, 15%). LC-MS (ESI): m / z 596.6 (M+H)+. Synthetic route of compound 78 Synthesis of compound 78-b At room temperature, to a reaction vial were added 3-c (200 mg, 0.48 mmol), (S)-4-N-Boc-2- methylpiperazine (192 mg, 0.96 mmol), 1,4-dioxane (10 mL), and DIPEA (248 mg, 1.92 mmol). After degassed and purged with nitrogen, the reaction mixture was stirred at 90 °C overnight. The reaction mixture was concentrated and the residue was purified by column chromatography (mobile phase: PE / EA 10 / 0 to 1 / 1) to give compound 78-b (230 mg, 83%). LC-MS (ESI): m / z 580.4 (M+H)+. Synthesis of compound 78-a At room temperature, to a microwave tube were added 78-b (100 mg, 0.17 mmol), tert-butyl 3- cyano-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)carbamate 108 mg, 0.26 mmol), bis(diphenylphosphine phenyl ether)palladium(II) dichloride ( 25 mg, 0.03 mmol), cesium carbonate (112 mg, 0.34 mmol) and toluene (2 mL). The mixture was degassed and purged with nitrogen and microwave stirred at 100 °C overnight. The reaction mixture was concentrated and the residue was purified by column chromatography (mobile phase: PE / EA 10 / 0 to 0 / 10) to give compound 78-a (70 mg, 49%). LC-MS (ESI): m / z 836.5 (M+H)+. Synthesis of compound 78 At room temperature, to a reaction vial were added 78-a (70 mg, 0.08 mmol), acetonitrile (15 mL), and HCl / 1,4-dioxane (1M, 4 mL). The resulting mixture was stirred at room temperature for 3 hours. Concentrate at room temperature, and the residue was adjusted to basic with a methanolic solution of ammonia and concentrated, then dissolved with methanol, and the residue was purified by prep- HPLC to give compound 78 (11 mg, 25%). LC-MS (ESI): m / z 536.4 (M+H)+. Synthetic route of compound 79 Synthesis of compound 79-b At room temperature, to a reaction vial were added 3-c (200 mg, 0.48 mmol), tert-butyl (S)-3- methyl-1,4-diazepane-1-carboxylate (206 mg, 0.96 mmol), 1,4-dioxane (10 mL) and DIPEA (248 mg, 1.92 mmol). After degassed and purged with nitrogen, the reaction mixture was stirred at 90 °C overnight. The reaction mixture was concentrated and the residue was purified by column chromatography (mobile phase: PE / EA 10 / 0 to 1 / 1) to give compound 79-b (240 mg, 84%). LC-MS (ESI): m / z 594.3 (M+H)+. Synthesis of compound 79-a At room temperature, to a microwave tube were added 79-b (100 mg, 0.17 mmol), tert-butyl (3- cyano-4-(5,5-dimethyl-1,3,2-dioxaborolan-2-yl)-7-fluorobenzo[b]thiophen-2-yl)carbamate(204 mg, 0.50 mmol), bis(diphenylphosphine phenyl ether) palladium(II) dichloride (24 mg.0.03 mmol), cesium carbonate (165 mg, 0.51 mmol) and toluene (2 mL). After degassed and purged with nitrogen, the mixture was microwaved at 120°C for 48 hours. The reaction mixture was concentrated and the residue was purified by column chromatography (mobile phase: PE / EA 10 / 0 to 0 / 10) to give compound 79-a (80 mg, 56%). Synthesis of compound 79 At room temperature, to a reaction vial were added 79-a (80 mg, 0.09 mmol), acetonitrile (15 mL) and HCl / 1,4-dioxane (1M, 4 mL). The reaction mixture was stirred at room temperature for 3 hours. Concentrate at room temperature, and the residue was adjusted to basic with a methanol solution of ammonia and concentrate, then dissolved with methanol, and the residue was purified by prep- HPLC to give compound 79 (8 mg, 15%). LC-MS (ESI): m / z 550.3 (M+H)+. Synthetic route of compound 80 Synthesis of compound 80-c At room temperature, to a reaction vial were added tert-butyl (S)-3-methyl-1,4-diazepane-1- carboxylate (400 mg, 1.87 mmol) and THF (10 mL). After degassed and purged with nitrogen, the above mixture was cooled down to 0 °C, was added a solution of lithium aluminum hydride in tetrahydrofuran (1 M, 5.6 mL) dropwise . The reaction mixture was stirred at room temperature for 48 hours, then was added sodium sulfate decahydrate and stirred for 1 h. The filtrate was filtered and the filter cake was washed with THF. The filtrate was concentrated to give the crude compound 80-c (300 mg). LC-MS (ESI): m / z 128.8 (M+H)+. Synthesis of compound 80-b At room temperature, to a reaction vial were added 3-c (388 mg, 0.93 mmol), 80-c (150 mg, 0.93 mmol), 1,4-dioxane (10 mL) and DIPEA (482 mg, 3.73 mmol). After degassed and purged with nitrogen, the reaction mixture was stirred at 90 °C overnight. The reaction mixture was concentrated and the residue was purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to give compound 80-b (150 mg, 32%). LC-MS (ESI): m / z 508.4 (M+H)+. Synthesis of compound 80-a At room temperature, to a microwave tube were added 80-b (150 mg, 0.30 mmol), tert-butyl (3- cyano-4-(5,5-dimethyl-1,3,2-dioxaborolan-2-yl)-7-fluorobenzo[b]thiophen-2-yl)carbamate (358 mg, 0.89 mmol), bis(diphenylphosphine phenyl ether) palladium(II) dichloride (42 mg.0.06 mmol), cesium carbonate (289 mg, 0.89 mmol) and toluene (3 mL). The mixture was degassed and purged with nitrogen, then microwaved at 120°C for 48 hours. The reaction mixture was concentrated and the residue was purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to give compound 80-a (70 mg, 31%). LC-MS (ESI): m / z 764.9 (M+H)+. Synthesis of compound 80 At room temperature, to a reaction vial were added 80-a (70 mg, 0.09 mmol), acetonitrile (15 mL) and HCl / 1,4-dioxane (1M, 4 mL). The reaction mixture was stirred at room temperature for 3 hours. Concentrate at room temperature, and the residue was adjusted to basic with a methanolic solution of ammonia, and concentrate, then dissolved with methanol, and the residue was purified by prep- HPLC to give compound 80 (2.7 mg, 5%). LC-MS (ESI): m / z 564.4 (M+H)+. Synthetic route of compound 81 Synthesis of compound 81-c To a reaction flask were added tert-butyl 3-bromo-5-chloro-4-trifluoromethylaniline formate (1 g, 2.67 mmol), dichloromethane (9 mL) and trifluoroacetic acid (3 mL, 40.04 mmol). The reaction mixture was stirred at room temperature for 1 hour, concentrated to dryness, diluted by adding dichloromethane / methanol (10:1, 10 mL), the pH was neutralized to 8-9 by adding saturated aqueous ammonium bicarbonate solution, partitioned, and the aqueous phase was extracted with dichloromethane / methanol (10:1, 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the residue was purified by column chromatography (mobile phase: ethyl acetate / petroleum ether=0-20%) to give compound 81-c (397 mg, 54%). LC-MS (ESI): m / z 273.9 (M+H)+. Synthesis of compound 81-b To a reaction flask in an ice-water bath was added 81-c (394 mg, 1.44 mmol), pinacol ester of bisboronic acid (1.094 g, 4.31 mmol), potassium acetate (423 mg, 4.31 mmol), Pd(dppf)Cl2-CH2Cl2(59 mg, 0.072 mmol) and 1,4- dioxane (6 mL). The mixture was degassed and purged with nitrogen for three times, then stirred at 90 °C for 2 hours. The reaction mixture was supplemented with Pd(dppf)Cl2-CH2Cl2(59 mg, 0.072 mmol), degassed and purged with nitrogen for three times, stirred at 90 ℃ for 1.5 hours. The reaction mixture was concentrated to dryness and the residue was purified by column chromatography (mobile phase: ethyl acetate: petroleum ether = 0-20%) to give compound 81-b (275 mg, 60%). LC-MS (ESI): m / z 321.9 (M+H)+. Synthesis of compound 81-a To a microwave tube were added 3-b (100 mg, 0.19 mmol), 81-b (78 mg, 0.24 mmol), [n-butylbis(1- adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) mesylate (27 mg, 0.04 mmol), potassium phosphate (118 mg, 0.56 mmol), tetrahydrofuran ( 1.0 mL) and water (0.2 mL). The reaction mixture was sealed, degassed and purged with nitrogen for three times, stirred at 65 °C for 1 hour. Dichloromethane (2 mL) and water (1 mL) were added to the reaction mixture, partitioned and the aqueous phase was extracted with dichloromethane (2 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness and the residue was purified by column chromatography (mobile phase: ethyl acetate: petroleum ether = 0-20%) to give compound 81-a (62 mg, 48%). LC-MS (ESI): m / z 698.2 (M+H)+. Synthesis of compound 81 To a solution of 81-a (70 mg, 0.10 mmol) in dichloromethane (2.4 mL) was added tert- butyldimethylsilyl trifluoromethanesulfonate (398 mg, 1.50 mmol) in an ice-water bath, and the mixture was stirred for 0.5 hr at 0-5 °C. The reaction mixture was added saturated aqueous sodium bicarbonate solution (4 mL), stirred at room temperature for 20 min, then was extracted with dichloromethane / methanol (10:1) (5 mL*2). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated to dryness, purified by column chromatography (mobile phase: methanol: dichloromethane=0-12%), concentrated, lyophilized to give compound 81 (38 mg, 63%). LC-MS (ESI): m / z 598.3 (M+H)+;1H NMR (400 MHz, d6-DMSO) δ 10.22 (s, 1H), 6.88 (d, J = 2.3 Hz, 1H), 6.48 (d, J = 2.3 Hz, 1H), 6.32 (s, 2H), 5.89 (t, J = 6.1 Hz, 1H), 5.32 (d, J = 54.3 Hz, 1H), 4.33 – 3.83 (m, 4H), 3.04 (t, J = 59.2 Hz, 6H), 2.22 – 1.99 (m, 3H), 1.97 – 1.76 (m, 5H), 1.75 – 1.59 (m, 4H). Synthetic route of compound 82 Synthesis of compound 82-d To a reaction flask were added methyl (2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)- carboxylate (400 mg, 2.14 mmol) and tetrahydrofuran (10 mL) . After stirred in an ice-water bath for 10 min, the reaction mixture was added lithium aluminum deuterium (126 mg, 2.99 mmol), and stirred for 12 h at room temperature. The reaction mixture was quenched by the addition of sodium sulfate decahydrate until no bubbles were emitted, filtered, and the filtrate was concentrated and the residue was purified by column chromatography (MeOH / DCM=0 / 100,1 / 10) to give compound 82- d (260 mg, 75%). LC-MS (ESI): m / z = 162.2 (M+H)+. Synthesis of compound 82-c To a reaction flask were added 82-d (260 mg, 1.61 mmol), dichloromethane (20 mL), 3-c (700 mg, 1.68 mmol), sodium tert-butoxide (162 mg, 1.68 mmol), respectively, and the mixture was stirred at 0 °C for 3 hr under protection of nitrogen. Water (20 mL) was added to the reaction mixture and the aqueous phase was extracted with dichloromethane (30 mL*3). The organic phase was concentrated and the residue was purified by column chromatography (MeOH / DCM=1 / 10) to afford compound 82-c (560 mg, 64%). LC-MS (ESI): m / z = 541.1(M+H)+. Synthesis of compound 82-b A reaction vial charged with 82-c (320 mg, 0.59 mmol), tetrahydrofuran (18 mL), water (2 mL), ((6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5- ((triisopropylmethylsilyl)ethynyl)naphthalen-2-yl)oxy)triisopropylsilane (554 mg, 0.89 mmol), potassium phosphate (439 mg, 2.07 mmol) and cataCXium A Pd G3 (2.48 mg, 0.003 mmol). After degassed and purged with nitrogen for three times, the reaction vial was placed in an oil bath prestirred at 60oC and stirred for 12 hours. The reaction mixture was concentrated to dryness and the residue was purified by column chromatography (mobile phase: methanol / dichloromethane = 0 / 100; 1 / 10) to give compound 82-b (270 mg, 54%). Synthesis of compound 82-a To a reaction flask, 82-b (270 mg, 0.32 mmol), DMF (20 mL) and cesium fluoride (800 mg, 5.27 mmol) were added. The reaction mixture was stirred at room temperature for 6 hours, then was added water (100 mL) and the aqueous phase was extracted with ethyl acetate (100 mL*3). The organic phase was concentrated and passed through the column layer (MeOH / DCM=0 / 100, 1 / 10) to give compound 82-a (170 mg, 77%). Synthesis of compound 82 A reaction vial charged with 82-a (170 mg, 0.25 mmol) and formic acid (20 mL) was stirred at room temperature for 6 hours. The reaction mixture was concentrated at room temperature and the residue was purified by prep-HPLC to afford compound 82 (32 mg, 22%), LC-MS (ESI): m / z 591.3(M+H)+. Synthetic route of compound 83 Synthesis of compound 83-h To a reaction flask, diethyl glutarate (3000 mg, 15.94 mmol) and tetrahydrofuran (60 mL) were added. Placed in an ice-water bath for 10 min, the above mixture was added lithium aluminum deuteride (1200 mg, 28.59 mmol), then stirred at room temperature for 12 hours. The reaction mixture was quenched by adding solid sodium decahydrate sulfate until no bubbles were released, filtered, and the organic phase was concentrated to give compound 83-h (1320 mg, 77%) which was directly used in the next step.1H NMR (400 MHz, CDCl3): δ 2.29 (s, 2H),1.62-1.53 (m, 4H), 1.49- 1.40 (m, 2H). Synthesis of compound 83-g To a reaction flask were added 83-h (1300 mg, 12.02 mmol), dichloromethane (40 mL), triethylamine (4864 mg, 48.07 mmol) and p-toluenesulfonyl chloride (6873 mg, 36.05 mmol), respectively. The reaction mixture was stirred overnight under protection of nitrogen, then was added water (20 mL). The aqueous phase was extracted with dichloromethane (50 mL*3). The organic phase was concentrated and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to afford compound 83-g (4036 mg, 81%). LC-MS (ESI): m / z = 434.7(M+NH4)+. Synthesis of compound 83-f To a reaction flask were added 83-g (4000 mg, 9.60 mmol), acetonitrile (100 mL), 2-(tert- butyl)hydrazine-1,2-dicarboxylic acid-1-benzyl ester (2711 mg, 10.18 mmol) and cesium carbonate (15644 mg, 48.02 mmol). After degassed and purged with nitrogen for three times, the reaction flask was placed into an oil bath preheated at 65oC and stirred for 36 hours. The reaction mixture was filtered. The organic phase was concentrated to dryness and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 3) to afford compound 83-f (2650 mg, 82%). LC-MS (ESI): m / z = 356.4(M+ NH4)+. Synthesis of compound 83-e To a reaction flask were added 83-f (2650 mg, 7.83 mmol), ethyl acetate (150 mL) and Pd / C (700 mg, l0%). After degassed and purged with hydrogen for three times, the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was filtered and the organic phase was concentrated to give compound 83-e (1400 mg, 88%). LC-MS (ESI): m / z = 205.3 (M+H)+. Synthesis of compound 83-d A reaction vial charged with 83-e (700 mg, 3.43 mmol), dichloromethane (30 mL), DIPEA (1329 mg, 10.28 mmol), 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (865 mg, 3.43 mmol) was stirred for 12 hr at this temperature and protected by nitrogen. The reaction mixture was quenched with saturated sodium bicarbonate (100 mL), extracted with dichloromethane (100 mL*2). The organic phase was concentrated and the residue was purified by column chromatography (PE / EA=10 / 1) to give compound 83-d (1400 mg, 97%). LC-MS (ESI): m / z = 420.3 (M+H)+. Synthesis of compound 83-c A reaction vial charged with 83-d (800 mg, 1.90 mmol), dichloromethane (30 mL), sodium tert- butoxide (366 mg, 3.81 mmol) and ((2R,7aS)-2-fluorohexahydro-1H-pyrrolozin-7a-yl)methanol (333 mg, 2.09 mmol) was stirred in an ice-water bath at atmosphere of nitrogen for 3 hr, then stirred at room temperature overnight. The reaction mixture was quenched by adding water (20 mL) and the aqueous phase was extracted with dichloromethane (50 mL*3). The organic phase was concentrated and the residue was purified by column chromatography (MeOH / DCM=1 / 10) to afford compound 83-c (890 mg, 86%). LC-MS (ESI): m / z = 543.7(M+H)+. Synthesis of compound 83-b 83-c (290 mg, 0.53 mmol), tetrahydrofuran (10 mL), water (1 mL), ((6-fluoro-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylmethylsilyl)ethynyl)naphthalen-2- yl)oxy)triisopropylsilane (500 mg, 0.80 mmol), potassium phosphate (397 mg, 1.87 mmol) and cataCXium A Pd G3 (78 mg, 0.11 mmol) were combined in a reaction vial. After degassed and purged with nitrogen for three times, the flask was placed in an oil bath preheated at 65oC and stirred for 12 hours. The reaction mixture was concentrated to dryness and the residue was purified by column chromatography (mobile phase: methanol / dichloromethane = 0 / 100; 1 / 10) to afford compound 83-b (460 mg, 86%). LC-MS (ESI): m / z =1005.5(M+H)+. Synthesis of compound 83-a To a reaction flask were added 83-b (460 mg, 0.46 mmol), DMF (5 mL) and cesium fluoride (695 mg, 4.58 mmol). The reaction mixture was stirred at room temperature for 6 hours, then was added water (60 mL) and the aqueous phase was extracted with ethyl acetate (60 mL*3). The organic phase was concentrated and the residue was purified by column layer (MeOH / DCM=0 / 100, 1 / 10) to give compound 83-a (270 mg, 85%). Synthesis of compound 83 A reaction vial charged with 83-a (200 mg, 0.29 mmol) and formic acid (10 mL) was stirred for 12 h at room temperature under protection of nitrogen. The reaction mixture was concentrated at room temperature and the residue was purified by prep-HPLC to afford compound 83 (50 mg, 29%), LC- MS (ESI): m / z 593.5(M+H)+. Synthetic route of compound 84 Synthesis of compound 84-h At room temperature, to a reaction vial were added 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3- d]pyrimidin-4(3H)-one (2500 mg, 8.93 mmol), phosphorus oxychloride (10 mL), DIPEA (3461 mg, 26.78 mmol).The reaction vial was placed in an oil bath preheated at 85oC and stirred for 3 hours. The reaction mixture was concentrated to dryness and the crude product was added ice-coldwater. The aqueous phase was extracted with dichloromethane (100 mL*3) and the organic phase was dried over sodium sulfate. Filtered and the organic phase was concentrated to give compound 84-h (1890 mg, 71%). Synthesis of compound 84-g At room temperature, to a reaction vial were added tert-butyl 1,2-diazepane-1-carboxylate (2730 mg, 13.63 mmol), 2-tert-butyldimethylsilyloxyacetaldehyde (4900 mg, 28.11 mmol) and methanol (80 mL). Placed in an ice-water bath, the reaction mixture was added sodium cyanoborohydride (4900 mg, 77.98 mmol) slowly, and stirred at room temperature for for 24 hours. The reaction mixture was concentrated, the residue was added water (100 mL) and the aqueous phase was extracted with ethyl acetate (100 mL*3). The organic phase was concentrated and the residue was purified by column chromatography (PE / EA=20 / 1) to afford compound 84-g (3910 mg, 80%). LC- MS (ESI): m / z = 359.4(M+H)+. Synthesis of compound 84-f To a reaction flask were added 84-g (800 mg, 2.23 mmol) and acetonitrile (10 mL), respectively. After stirred under protection of nitrogen in an ice-water bath for 10 min, the reaction mixture was added hydrochloride / 1,4-dioxane (4M, 1 mL, 4.00 mmol) dropwise and stirred in an ice-water bath for 4 hours. Placed in an ice-water bath, the reaction mixture was added ammonia methanol (2 mL, 14.00 mmol, 7 M). Concentrated and the residue was purified by column chromatography (MeOH / DCM = 0 / 100, 1 / 10) to give compound 84-f (70 mg, 12%). LC-MS (ESI): m / z = 259.3(M+H)+. Synthesis of compound 84-e To a reaction flask were added 84-h (196 mg, 0.66 mmol), dichloromethane (20 mL), DIPEA (255 mg, 1.97 mmol) and the mixture was stirred at -78oC for 10 min, then was added 84-f (170 mg, 0.66 mmol) and stirred at -78oC for half an hour, then stirred for 2 hours at room temperature. The reaction mixture was concentrated at room temperature and the residue was added saturated sodium bicarbonate solution (30 mL). The aqueous phase was extracted with dichloromethane (30 mL*2). The organic phase was concentrated and the residue was purified by column chromatography (PE / EA=10 / 1) to afford compound 84-e (249 mg, 73%). LC-MS (ESI): m / z = 520.3 (M+H)+. Synthesis of compound 84-d A reaction flask charged with 84-e (249 mg, 0.48 mmol), DMF (5 mL) and cesium fluoride (220 mg, 1.45 mmol) was stirred at 55oC for 3 hours under protection of nitrogen. The reaction mixture was added water (50 mL), extracted with ethyl acetate (50 mL*3), purified by column chromatography (MeOH / DCM=0 / 100, 1 / 10) to give compound 84-d (143 mg, 81%). LC-MS (ESI): m / z = 370.2 (M+H)+. Synthesis of compound 84-c At room temperature, to a reaction vial were added 84-d (140 mg, 0.38 mmol), ethyl acetate (20 mL) and m-chloroperoxybenzoic acid (192 mg, 0.95 mmol, 85%). After stirred at 0oC for 2 hrs, the reaction mixture was then stirred at room temperature for another 1 hr. The reaction mixture was added saturated sodium bicarbonate solution (100 mL) and the aqueous phase was extracted with ethyl acetate (50 mL*2). The organic phase was concentrated and the residue was purified by column chromatography (PE / EA=3 / 1, 0 / 100) to give compound 84-c (130 mg, 85%). LC-MS (ESI): m / z = 402.1 (M+H)+. Synthesis of compound 84-b A reaction vial charged with ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methanol (68 mg, 0.43 mmol), 84-c (130 mg, 0.32 mmol), toluene (10 mL) and sodium tert-butoxide (50 mg, 0.52 mmol) was stirred for 3 h at room temperature under protection of nitrogen. The reaction mixture was mixed with silica gel and purified by column chromatography (MeOH / DCM = 0 / 100, 1 / 10) to give compound 84-b (96 mg, 62%). LC-MS (ESI): m / z = 481.3(M+H)+. Synthesis of compound 84-a A reaction vial charged with 84-b (96 mg, 0.20 mmol), tetrahydrofuran (6 mL), potassium phosphate (169 mg, 0.80 mmol), water (0.8 mL), cataCXium A Pd G3 (44 mg, 0.06 mmol) and ((6-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -yl)-5-((triisopropylmethylsilyl)ethynyl)naphthalen-2- yl)oxy)triisopropylsilane (249 mg, 0.40 mmol) was degassed and purged with nitrogen for three times, then placed in an oil bath preheated at 65oC and the reaciton mixture was stirred for 12 hours. The reaction mixture was concentrated to dryness and the residue was purified by column chromatography (mobile phase: methanol / dichloromethane = 0 / 100; 1 / 10) to give compound 84-a (110 mg, 58%). Synthesis of compound 84 To a reaction flask were added 84-a (90 mg, 0.10 mmol), DMF (5 mL) and cesium fluoride (145 mg, 0.95 mmol). The reaction mixture was stirred at room temperature for 6 hours, then was added water (50 mL), extracted with ethyl acetate (50 mL*2), concentrated, and the residue was purified by prep-HPLC to obtain compound 84 (39 mg, 65%). LC-MS (ESI): m / z = 631.3 (M+H)+;1H NMR (400 MHz, DMSO-d6): δ 10.15 (1H, brs), 7.99-7.92 (1H, m), 7.49-7.42 (1H, m), 7.38-7.33 (1H, m), 7.26-7.04 (1H, m), 5.28 (1H, d, J = 54.0Hz), 4.60-3.93 (6H, m), 3.59-3.33 (3H, m), 3.18 – 2.95 (5H, m), 2.93 – 2.73 (2H, m), 2.25 – 1.93 (4H, m), 1.90 –1.63 (7H, m). Synthetic route of compound 85 Compound 85-d was synthesized according to the method of Patent CN116891488A. Synthesis of compound 85-c 85-d (170 mg, 0.63 mmol), dichloromethane (20 mL), 3-c (391 mg, 0.94 mmol) and sodium tert- butoxide (121 mg, 1.25 mmol) were added to a reaction flask at room temperature. After stirred for 3 hours at 0°C under protection of nitrogen, the reaction mixture was added saturated ammonium chloride (100 mL) to and the aqueous phase was extracted with dichloromethane (50 mL*2). The organic phase was concentrated and the residue was purified by column chromatography (PE / EA=10 / 1, 3 / 1) to give compound 85-c (290 mg, 71%). Synthesis of compound 85-b To a microwave tube were added 85-c (170 mg, 0.26 mmol), tetrahydrofuran (6 mL), water (0.8 mL), ((6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5- ((triisopropylmethylsilyl)ethynyl)naphthalen-2-yl)oxy)triisopropylsilane (326 mg, 0.52 mmol), potassium phosphate (166 mg, 0.78 mmol) and cataCXium A Pd G3 (57 mg, 0.08 mmol). After degassed and purged with nitrogen for three times, the microwave tube was placed in an oil bath preheated at 65oC and stirred for 8 hours. The reaction mixture was concentrated and the residue was purified by column chromatography (PE / EA = 5 / 1, 1 / 1) to afford compound 85-b (226 mg, 78%). LC-MS (ESI): m / z = 1113.4(M+H)+. Synthesis of compound 85-a To a reaction flask were added 85-b (230 mg, 0.21 mmol), DMF (5 mL) and cesium fluoride (1300 mg, 8.56 mmol). The reaction mixture was stirred at room temperature under protection of nitrogen for 10 h, then was added ammonium chloride (100 mL) and the aqueous phase was extracted with ethyl acetate (100 mL*3). The organic phase was concentrated and the residue was purified by column chromatography (PE / EA=100 / 0, 3 / 1) to afford compound 85-a (133 mg, 80%). LC-MS (ESI): m / z = 801.4(M+H)+. Synthesis of compound 85 To a reaction flask were added 85-a (130 mg, 0.16 mmol) and dichloromethane (6 mL). After stirred in an ice-water bath for 10 min, the reaction mixture was added TBSOTf (20 mg, 0.08 mmol) slowly and stirred in an ice-water bath for 1 hr. The reaction mixture was added saturated aqueous sodium bicarbonate (50 mL), stirred at room temperature for 17 h. The reaction mixture was extracted with dichloromethane (20 mL*3). The organic phase was concentrated and the residue was purified by prep-HPLC to afford compound 85 (68 mg, 60%). LC-MS (ESI): m / z 701.1(M+H)+. Synthetic route of compound 86 Synthesis of compound 86-d Synthesized according to the method of Patent CN116891488A. Synthesis of compound 86-c 86-d (120 mg, 0.44 mmol), dichloromethane (20 mL), 3-c (276 mg, 0.66 mmol) and sodium tert- butoxide (164 mg, 0.66 mmol) were added to a reaction flask at room temperature. After stirred for 3 hours at 0°C under protection of nitrogen, the reaction mixture was added saturated ammonium chloride (100 mL) and the aqueous phase was extracted with dichloromethane (50 mL*2). The organic phase was concentrated and the residue was purified by column chromatography (DCM / MeOH=100 / 0, 20 / 1) to afford compound 86-c (159 mg, 55%). LC-MS (ESI): m / z = 651.1(M+H)+. Synthesis of compound 86-b To a microwave tube were added 86-c (159 mg, 0.24 mmol), tetrahydrofuran (6 mL), water (0.8 mL), ((6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5- ((triisopropylmethylsilyl)ethynyl)naphthalen-2-yl)oxy)triisopropylsilane (305 mg, 0.49 mmol), potassium phosphate (156 mg, 0.73 mmol) and cataCXium A Pd G3 (53 mg, 0.07 mmol). After degassed and purged with nitrogen for three times, it was placed in an oil bath preheated at 65oC and stirred for 8 hours. The reaction mixture was concentrated and the residue was purified by column chromatography (DCM / MeOH = 100 / 0, 20 / 1) to afford compound 86-b (196 mg, 72%). LC-MS (ESI): m / z = 1113.4(M+H)+. Synthesis of compound 86-a To a reaction flask were added 86-b (196 mg, 0.18 mmol), DMF (5 mL) and cesium fluoride (1300 mg, 8.56 mmol). After stirred at room temperature under protection of nitrogen for 10 h, the reaction mixture was added ammonium chloride (100 mL) and the aqueous phase was extracted with ethyl acetate (100 mL*3). The organic phase was concentrated and the residue was purified by column chromatography (DCM / MeOH=100 / 0, 10 / 1) to afford compound 86-a (134 mg, 95%). LC-MS (ESI): m / z = 801.6(M+H)+. Synthesis of compound 86 To a reaction flask were added 86-a (90 mg, 0.11 mmol) and dichloromethane (6 mL). After stirred in an ice-water bath for 10 min, the reaction mixture was added TBSOTf (20 mg, 0.08 mmol) slowly and stirred in an ice-water bath for 1 hr. The reaction mixture was added saturated aqueous sodium bicarbonate (50 mL), stirred at room temperature for 17 h. The reaction mixture was extracted with dichloromethane (20 mL*3). The organic phase was concentrated and the residue was purified by prep-HPLC to give compound 86 (40 mg, 51%), LC-MS (ESI): m / z 701.3(M+H)+. Synthetic route of compound 87

[0022] Synthesis of compound 87-f Phosphorus oxychloride (1.31 g, 8.57 mmol) and N,N - diisopropylethylamine (3.0 mL, 17.14 mmol) were added to a reaction vial charged with 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3- d]pyrimidin-4(1H)-one (2 g, 7.14 mmol) and acetonitrile (30 mL) under the protection of nitrogen. The reaction mixture was stirred at 85 °C for 1 hour, then was cooled to -10 °C, was added a solution of 1,2-diazepane-1-carboxylic acid tert-butyl ester (1.43 g, 7.14 mmol)in acetonitrile solution (10 mL) and N,N-diisopropylethylamine (0.55 g, 4.28 mmol), then stirred for 1 h at room temperature and concentrated to dryness. The residue was added water (30 mL), stirred for 15 min, diluted with ethyl acetate (30 mL), and the aqueous phase was then extracted with ethyl acetate (20 mL). The organic phases were combined, washed with brine(30 mL), dried over anhydrous sodium sulfate, and the residue was purified by column chromatography (mobile phase: ethyl acetate / petroleum ether = 0-20%) to give compound 87-f (2.89 g, 87%). LC-MS (ESI): m / z 461.9 (M+H)+. Synthesis of compound 87-e A reaction vial charged with 87-f (500 mg, 1.08 mmol), potassium vinyl trifluoroborate (188 mg, 1.41 mmol), sodium bicarbonate (218 mg, 2.60 mmol), tetrakis(triphenylphosphine)palladium (125 mg, 0.11 mmol) and ethanol (5 mL) was degassed and purged with nitrogen for three times, stirred at 80 °C for 5 hours. Dichloromethane (20 mL) and water (20 mL) were added to the reaction mixture. Partitioned, the aqueous phase was extracted with dichloromethane (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness and the residue was purified by column chromatography (mobile phase: ethyl acetate: petroleum ether = 0-80%) to give compound 87-e (210 mg). LC-MS (ESI): m / z 454.4 (M+H)+. Synthesis of compound 87-d 87-e (210 mg, 0.19 mmol, 40% purity), trifluoroacetic acid (2 mL) and dichloromethane (2 mL) were added to a reaction vial and the reaction mixture was stirred at room temperature for 1 hour. Removed the organic solvent by rotary evaporation. The residue was added dichloromethane (10 mL) and water (10 mL), neutralized to pH 8-9 with saturated sodium bicarbonate. Partitioned, the aqueous phase was extracted with dichloromethane (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness, and the residue was purified by column chromatography (mobile phase: ethyl acetate: petroleum ether = 0- 80%) to give compound 87-d (50 mg, 13% in two-step reaction). LC-MS (ESI): m / z 354.1 (M+H)+. Synthesis of compound 87-c To a reaction flask charged with 87-d (240 mg, 0.68 mmol) and dichloromethane (2 mL) was added m-chloroperoxybenzoic acid (151 mg, 0.75 mmol) in an ice-water bath. The reaction mixture was stirred at 0-5°C for 1 h, then was added saturated sodium bicarbonate to pH 9-10, then dichloromethane (10 mL). Partitioned, the aqueous phase was extracted with dichloromethane (10 mL). The organic phases were combined, washed with brine(10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to give compound 87-c (260 mg, 100%). LC-MS (ESI): m / z 370.1 (M+H)+. Synthesis of compound 87-b A solution of ((2R,7aS)-2-fluorohexahydro-1H-pyrrolylazin-7a-yl)methanol (124 mg, 0.78 mmol) in anhydrous tetrahydrofuran (2.5 mL) was added into a solution of sodium tert-butoxide (81 mg, 0.85 mmol) in anhydrous toluene (1 mL) dropwise at -10 to -5°C. The mixture was stirred at -10 °C for 30 min, then was added a solution of 87-c ( 250 mg, 0.68 mmol) in anhydrous tetrahydrofuran solution (10 mL) dropwise, and stirred at -10 to -5 °C for 1 hour. It was quenched by addition of brine (5 mL), stirred for 10 min and extracted twice with ethyl acetate (10 mL). The organic phases were combined, filtered, and the filtrate was concentrated to dryness and the residue was purified by column chromatography (mobile phase: methanol: dichloromethane = 0-5%) to give compound 87-b (153 mg). LC-MS (ESI): m / z 464.9 (M+H)+. Synthesis of compounds 87-a-1 and 87-a-2 To a microwave tube were added 87-b (60 mg, 0.13 mmol), ((6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-5-((triisopropylmethylsilyl)ethynyl)naphthalen-2-yl)oxy)triisopropylsilane (97 mg, 0.16 mmol), methanesulfonated [butylbis(1-adamantyl)phosphine ](2-amino-1,1'-biphenyl-2- yl)palladium(II) (14 mg, 0.02 mmol), potassium phosphate (82 mg, 0.39 mmol), tetrahydrofuran (2.0 mL) and water (0.4 mL). The reaction mixture was sealed, degassed and purged with nitrogen for three times and microwaved at 90 °C for 6 hours. The reaction mixture was extracted twice with dichloromethane (5 mL). The organic phases were combined, filtered, and the filtrate was concentrated to dryness. The residue was purified by column chromatography (mobile phase: ethyl acetate: petroleum ether = 10-100%; methanol: dichloromethane = 0-8%) to obtain 87-a-1 (45 mg) and 87-a-2 deprotected of TIPS (89 mg, 42% purity). 87-a-1: LC-MS (ESI) : m / z 927.3 (M+H)+. 87-a-2: LC-MS (ESI): m / z 771.2 (M+H)+. Synthesis of compound 87 To a solution of 87-a-1 (45 mg, 0.05 mmol) in tetrahydrofuran (2.4 mL) was added tetrabutylammonium fluoride trihydrate (39 mg, 0.13 mmol). The resulting mixture was stirred at room temperature for 2 hours. To a solution of 87-a-2 (89 mg, 42% purity, 0.05 mmol) in tetrahydrofuran (2 mL) was added tetrabutylammonium fluoride trihydrate (39 mg, 0.13 mmol) and the mixture was stirred at room temperature for 2 hours. The reaction mixtures were combined, was added dichloromethane (10 mL) and water (10 mL). Partitioned, the aqueous phase was extracted with dichloromethane (10 mL). The organic phases were combined, anhydrous sodium sulfate was dried, filtered, concentrated to dryness, and the residue was purified by column chromatography (mobile phase: methanol: dichloromethane = 0-8%), concentrated, lyophilized to give compound 87 (43 mg). LC-MS (ESI): m / z 615.7 (M+H)+. Synthetic route of compound 88 Synthesis of compound 88-e A reaction vial were added N-Boc-piperazine (2.23 g, 11.96 mmol), 3,5-difluoro-4- trifluoromethylbromobenzene (2.23 g, 8.54 mmol), tris(dibenzylideneacetone)dipalladium (780 mg, 0.85 mmol), 1,3-bis(2,6-diisopropylphenyl)imidazole chloride (730 mg, 1.71 mmol) , sodium tert- butoxide (1.23 g, 12.81 mmol) and toluene (22 mL). After degassed and purged with nitrogen for three times, the reaction mixture was stirred at 100 °C for 2 hours. Cooled to room temperature, the reaction mixture was added water (50 mL), ethyl acetate (50 mL). Partitioned, and the aqueous phase was extracted with ethyl acetate (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness, and the residue was purified by column chromatography (mobile phase: ethyl acetate: petroleum ether = 0-10%) to give compound 88-e (2.30 g, 73%). LC-MS (ESI): m / z 367.1 (M+H)+. Synthesis of compound 88-d To a reaction vial were added 88-e (3.00g, 8.19mmol), dichloromethane (30mL) and trifluoroacetic acid (14.00g, 123mmol), and the above mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated and then was added dichloromethane (50mL), and was adjusted pH to 9- 10 with saturated aqueous sodium carbonate, and the organic phase was concentrated to give compound 88-d (2.00g 92%). LC-MS(ESI): m / z 267.1 (M+H)+. Synthesis of compound 88-c To a reaction flask were added 3-c (2 g, 4.80 mmol) and 1,1-cyclopropanedimethanol (2.14 g, 20.95 mmol), N,N-dimethylformamide (10 mL) and tetrahydrofuran (10 mL). After warmed up to 50°C, the above mixture was added cesium carbonate (5.4 g, 16.57 mmol) and DABCO (0.054 g, 0.48 mmol), and stirred at 50 °C for 1 hour. The reaction mixture was cooled to room temperature, was added water (100 mL). A large amount of solid was precipitated, and pulped at room temperature for 30 min, filtered, and the filter cake was dried to obtain 88-c (2.00 g, 86%). LCMS (ESI): m / z 482.1 (M+H)+. Synthesis of compound 88-b To a reaction flask in an ice-water bath was added 88-c (800 mg, 1.66 mmol), dichloromethane (10 mL), triethylamine (504 mg, 4.98 mmol), followed by dropwise addition of methylsulfonyl chloride (190 mg, 1.66 mmol) in dichloromethane (2 mL), and the reaction mixture was stirred in ice-water bath for half an hour. The reaction mixture was added water (30 mL), extracted with dichloromethane (30 mL), and the organic phase was dried and concentrated to give compound a clear oil. To the oil was added potassium iodide (827 mg, 4.98 mmol), triethylamine (504 mg, 4.98 mmol), 88-d (442 mg, 1.66 mmol), N,N-dimethylformamide (10 mL), and the mixture was stirred at 90 °C for 2 hours. Water (40 mL) was added to the reaction mixture and the aqueous phase was extracted twice with ethyl acetate (20 mL). The organic phases were combined, washed with brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and the residue was purified by column chromatography (mobile phase: ethyl acetate: petroleum ether = 0-20%) to give compound 88-b (600 mg, 50%). LCMS(ESI):m / z 730.5 (M+H)+. Synthesis of compound 88-a A reaction vial were added 88-b (400 mg, 0.55 mmol), ((6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-5-((triisopropylmethylsilyl)ethynyl)naphthalen-2-yl)oxy)triisopropylsilane (342 mg, 0.55 mmol), methanesulfonic acid [n-butylbis(1-adamantyl ) phosphine](2-amino-1,1 '- biphenyl-2-yl)palladium(II) (40 mg, 0.06 mmol), potassium phosphate (349 mg, 1.64 mmol), tetrahydrofuran (10 mL) and water (2 mL). After degassed and purged with nitrogen, the reaction mixture was stirred at 60°C for 2.5 hours. Water (20 mL) was added to the reaction mixture and the aqueous phase was extracted with ethyl acetate (30 mL). The organic phase was concentrated to give a black crude compound (550 mg). The black crude was dissolved directly in N,N- dimethylformamide (10 mL), was added CsF (1.00 g, 6.58 mmol) and stirred at room temperature for 2 hours. To the reaction mixture, water (20 mL) was added and the aqueous phase was extracted twice with ethyl acetate (20 mL). The organic phases were combined, washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, concentrated, and the residue was purified by column chromatography (mobile phase: ethyl acetate: petroleum ether = 0-60%) to give compound 88-a (75 mg, 16%). LCMS (ESI): m / z 880.3 (M+H)+. Synthesis of compound 88 Tert-butyldimethylsilyl trifluoromethanesulfonate (270 mg, 1.02 mmol) was added dropwise to a solution of 88-a (60 mg, 0.07 mmol) in dichloromethane (1.6 mL) in an ice-water bath, and the mixture was stirred for 40 min at 0-5 °C, then was added saturated aqueous sodium bicarbonate (4 mL) and stirred at room temperature overnight. The mixture was extracted with dichloromethane / methanol (10:1) (10mL*2). The organic pahse was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness purified over column (mobile phase: ethyl acetate: petroleum ether = 10-80%) to obtain the crude product (40mg), purified by prep- HPLC (mobile phase Acetonitrile: 10mM aqueous ammonium bicarbonate = 10-75%), concentrated, lyophilized to obtain compound 88 (28mg, 53%). LC-MS (ESI): m / z 780.4 (M+H)+;1H NMR (400 MHz, CDCl3) δ 10.16 (s, 1H), 7.51 – 7.41 (m, 1H), 7.25 – 7.18 (m, 1H), 7.09 (t, J = 8.8 Hz, 1H), 7.00 (s, 1H), 6.28 (d, J = 13.5 Hz, 2H), 4.47 (d, J = 10.8 Hz, 1H), 4.33 – 4.20 (m, 2H), 4.10 – 3.96 (m, 2H), 3.32 – 2.94 (m, 7H), 2.85 – 2.29 (m, 7H), 1.98 – 1.88 (m, 2H), 1.78 – 1.60 (m, 4H), 0.79 – 0.63 (m, 2H), 0.61 – 0.39 (m, 2H). Synthetic route of compound 89 Synthesis of compound 89 Compound 4 (1 g, 1.70 mmol), DMF (20 mL) and potassium carbonate (704 mg, 5.10 mmol) were added to a reaction flask at room temperature, and the above mixture was added dimethylcarbamoyl chloride (235 uL, 2.55 mmol) dropwise while stirring. After the drop was completed, the reaction mixture was stirred at room temperature under protection of nitrogen for 2 h. The reaction mixture was quenched with water and the aqueous phase was extracted twice with ethyl acetate. The organic phase was washed three times with brine, dried over anhydrous sodium sulfate, concentrated to dryness by rotary evapoation, and the residue was purified by column chromatography (mobile phase: MeOH / DCM, 0-10%) to give compound 89 (990 mg, 88%). LC-MS (ESI): m / z 660.8 (M+H)+;1H NMR(400M, DMSO-d6): δ 10.27(1H, s), 8.24-8.14(1H, m), 7.97(1H, d, J=2.0Hz), 7.63(1H, t, J=8.8Hz), 7.48(1H, d, J=2.4Hz), 5.89(1H, t, J=6.0Hz), 5.31(1H, d, J=54.0Hz), 4.26-3.88(5H, m), 3.19-2.98(8H, m), 2.94(3H, s), 2.89-2.79 (1H, m), 2.20-1.56 (12H, m). Synthesis of compound 90 Referring to the synthetic route of compound 89, compound 90 was obtained using 4-morpholine carbonyl chloride instead of dimethylcarbamoyl chloride. LC-MS (ESI): m / z 702.8 (M+H)+. Synthetic route of compound 91

[0023] Synthesis of compound 91-b Compound 2-(2-(2-methoxyethoxy)ethoxy)ethanamine (1.00 g, 6.13 mmol) and DMAP (1.5 g, 12.25 mmol) were dissolved in 25 mL of anhydrous acetonitrile at room temperature and then the mixture was added dropwise to a solution of bis(p-nitrophenyl) carbonate (1.96 g, 6.43 mmol) in anhydrous acetonitrile solution (25 mL) in an ice-water bath. The reaction mixture was stirred under protection of nitrogen at 0oC for 30 minutes, then at room temperature for 1 hour. The reaction mixture was concentrated at reduced pressure and the residue was purified by flash column chromatography (EA / PE = 0-100%) to give compound 91-b (1.6 g, 80%). LC-MS (ESI): m / z = 329.1[M+H]+. Synthesis of compound 91-a Compound 91-b (381 mg, 1.16 mmol) was dissolved in 40 mL of anhydrous acetonitrile at room temperature, followed by addition of compound 12 (200 mg, 0.29 mmol) and DMAP (160 mg, 1.31 mmol) and the reaction mixture was stirred under protection of nitrogen at 50oC overnight. The reaction mixture was concentrated at reduced pressure and the residue was dissolved in 100 mL of ethyl acetate, washed sequentially with water (100 mL), 10% NaHSO4(100 mL), saturated sodium bicarbonate solution (100 mL), brine (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated at reduced pressure and the residue was purified by a flash column chromatography (MeOH / DCM = 0-10%) to afford compound 91-a (150 mg, 59%). LC-MS (ESI): m / z = 878.5[M+H]+. Synthesis of compound 91 Compound 91-a (150 mg, 0.17 mmol) was dissolved in 6 mL of anhydrous DCM at room temperature, then TFA (2 mL) was added and the reaction mixture was stirred under protection of nitrogen for 4 h at room temperature. The reaction mixture was concentrated at reduced pressure and the residue was suspended in saturated sodium bicarbonate solution (100 mL) and the aqueous phase was extracted with DCM (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated at reduced pressure, and the residue was purified by Prep-TLC (MeOH / DCM = 1:10) to afford compound 91 (108 mg, 82%). LC-MS (ESI): m / z = 778.3[M+H]+. Synthetic route of compound 92 Synthesis of compound 92-a To a solution of bis(p-nitrophenyl) carbonate (766 mg, 2.52 mmol) in acetonitrile (20 mL) was added 1-(2-aminoethoxy)-2-methoxyethane (300 mg, 2.52 mmol) and 4-dimethylaminopyridine (615 mg, 5.04 mmol) in acetonitrile (20 mL) dropwise at room temperature. After heated to 50oC, the reaction was allowed to proceed for 1 hour, then was added compound 12 (100 mg, 0.15 mmol) and stirred at 50oC under protection of nitrogen overnight. The next day, removed acetonitrile by rotary evaporation, added 10% NaHSO4solution and a small amount of anhydrous sodium sulfate and extracted five times with ethyl acetate. The organic phase was dried, concentrated to dryness by rotary evaporation, dissolved in a small amount of dichloromethane, and the residue was purified by column chromatography (mobile phase: methanol / dichloromethane, 0-10%) to give compound 92-a (111 mg, 92%). LC-MS (ESI): m / z 834.0(M+H)+. Synthesis of compound 92 Trifluoroacetic acid (1 mL) was added to a solution of 92-a (111 m...

Claims

What is claimed is:

1. A nitrogen-containing heterocyclic compound of formula I, a pharmaceutically acceptable salt thereof, a prodrug thereof, a stereoisomer thereof, a tautomer thereof or an isotopically labeled compound thereof:wherein “ “ represents a single or double bond;is phenyl, “5- to 7-membered heterocycloalkenyl containing 1–3 heteroatoms independently selected from O, S and N”, “5- to 7-membered heteroaryl containing 1–3 heteroatoms independently selected from O, S and N” or 5- to 7-membered cycloalkenyl; wherein D1is C, CH or N; D2is, wherein Z1and Z2are independently a bond, CH, CH2, O, S, N or NH; r is 0, 1, 2, 3 or 4; R5is independently deuterium, halogen, C1-6alkyl, C1-6alkyl substituted with one or more halogen, C3-10cycloalkyl, hydroxyl, C1-6alkyl-O-, C1-6alkyl-S-, amino, C1-6alkyl-NH-, C2-6alkenyl, nitro or C3-10cycloalkyl-O-; X1and X2are independently CRbor N, and X1and X2are not both CRb; Y1is O, S, NH, CH2orY2is NR2, O or S; m1, m2 and n are independently 0, 1, 2, 3 or 4; Rbis hydrogen, halogen or cyano;R1is C6-20aryl, “5- to 12-membered heteroaryl containing 1–4 heteroatoms independently selected from O, S and N”, C6-20aryl substituted with one or more R1-1or “5- to 12-membered heteroaryl containing 1–4 heteroatoms independently selected from O, S and N” substituted with one or more R1-2; provided that when multiple substituents are present, the substituents are the same or different; R1-1and R1-2are independently deuterium, halogen, -ORc, cyano, azide, -C(=O)R11, -NR12R13, - C(=O)OR14, -C(=O)NR15R16, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -B(ORx) (ORy), “4- to 7-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O, S and N”, C6-20aryl, “5- to 7-membered heteroaryl containing 1 or 2 heteroatoms independently selected from O, S, and N”, C1-6alkyl substituted by one or more R1-1-1, C1-6alkyl-O- substituted by one or more R1-1-2, C3-10cycloalkyl substituted by one or more R1-1-3, “4- to 7-membered heterocyclic cycloalkyl containing 1 or 2 heteroatoms independently selected from O, S, and N” substituted by one or more R1-1-4, C6-20aryl substituted with one or more R1-1-5, or “5- to 7-membered heteroaryl containing one or two heteroatoms independently selected from O, S, and N” substituted with one or more R1-1-6; provided that when multiple substituents are present, the substituents are the same or different; or, when the number of R1-1or R1-2is more than one, two optional R1-1or R1-2are connected, together with the atoms on the ring to which they are attached, independently form 3- to 8-membered cyclic olefin; R2, Rc, R12and R13are independently hydrogen, C1-6alkyl, -C(=O)Rc1, -C(=O)ORc2, - C(=O)NRc3Rc4, -SO2Rc5, , or C1-6alkyl substituted with one or more Rc10;Rc1, Rc2, Rc3, Rc4, Rc5, Rc6, Rc7, Rc8and Rc9are independently hydrogen, C1-20alkyl, C3-10cycloalkyl, “4- to 7-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O, S and N”, C6-20aryl, “5- to 7-membered heteroaryl containing 1 or 2 heteroatoms independently selected from O, S and N”, C1-20alkyl substituted with one or more R4-1-1, C3-10cycloalkyl substituted with one or more R4-1-2, “4- to 7-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O, S and N” substituted with one or more R4-1-3, C6-20aryl substituted with one or more R4-1-4, “5- to 7-membered heteroaryl containing 1 or 2 heteroatoms independently selected from O, S and N”, “5- to 7-membered heteroaryl containing 1 or 2heteroatoms independently selected from O, S and N” substituted with one or more R4-1-5, - NRc51Rc52, -(C1-6alkylene-O)p- C1-6alkyl, ; p is 1, 2,3 or 4;R1-1-1, R1-1-2, R1-1-3, R1-1-4, R1-1-5, R1-1-6, R4-1-1, R4-1-2, R4-1-3, R4-1-4and R4-1-5are independently cyano, halogen, hydroxyl, nitro, C1-6alkyl-O-, C1-6alkyl, C1-6alkyl substituted with one or more R31, C3-10cycloalkyl, “4- to 7-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O, S, and N”, C6-20aryl, “5- to 7-membered heteroaryl containing 1 or 2 heteroatoms independently selected from O, S, and N”, - B(ORx) (ORy), -C(=O)R21, -NR22R23, -C(=O)OR24, - OC(=O)R32, -C(=O)NR25R26, -COOH, -C(=O)OR27or -OC(=O)OR28; Rc10is -OC1-6alkyl, hydroxyl substituted with C1-6alkyl, C6-20aryl substituted with one ormore -B(ORx)(ORy), “5- to 7-membered heteroaryl containing 1 or 2 heteroatoms independently selected from O, S, and N” substituted with one or more Rc10-1,29 c10-1or -OC(=O)R ; Ris independently C1-6alkyl or nitro; or, optional R2and Rb, optional R2and R5together with the atoms to which they are attached, independently form “5- to 12-membered heterocyclic alkenyl containing 2 to 4 heteroatoms, two of which are N, and the other heteroatoms independently selected from O, S, and N”, or “5- to 12- membered heterocyclic alkenyl containing 2 to 4 heteroatoms, two of which are N, and the other heteroatoms independently selected from O, S, and N,” substituted with one or more Ra; Rxand Ryare independently hydrogen, C1-6alkyl, or Rxand Ryeach with the attached oxygen atom form five-membered ring substituted with one or more C1-6alkyl; R4is independently deuterium, halogen, cyano, hydroxyl, C1-6alkyl, C1-6alkyl substituted with one or more R4-1, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C1-6alkyl-O-, -O-C1-6alkyl substituted R4gwith one or more R4-2, -S-C1-6alkyl, -S-C1-6alkyl substituted with one or more R4-3, O=,, - O-C3-10cycloalkyl, -C(=O)R4a, -NR4b1R4b2, -C(=O)OR4cor -C(=O)NR4d1R4d2; or, when n is 2, 3 or 4, two optional R4are connected, together with the atoms to which they are attached form 3- to 8-membered carbocyclic ring, 3- to 8-membered carbocyclic ring substituted with one or more R4-4, “4- to 8-membered heterocyclic ring containing 1 to 3 heteroatoms independently selected from O, S, and N”, or, “4- to 8-membered heterocyclic ring containing 1 to 3 heteroatoms independently selected from O, S, and N” substituted with one or more R4-5; R4-1, R4-2, R4-3, R4-4, R4-5and Raare independently halogen, C1-6alkyl, C2-6alkenyl, cyano, hydroxyl, C1-6alkyl-O-, -NR4iR4j, -C(=O)OR4eor -C(=O)NR4f1R4f2; or, R4-5is O=; R4a, R4b1, R4b2, R4c, R4d1, R4d2, R4e, R4f1, R4f2, R4iand R4jare independently hydrogen, C1-6alkyl or C2-6alkenyl; L1is a bond, C1-6alkylene, -C(=O)-, -O(RL-1)n1-, -S(RL-2)n2- or -NRL-3(RL-4)n3-; RL-1, RL-2and RL-4are independently C1-6alkylene or C1-6alkylene substituted with one or more deuterium ; RL-3is hydrogen or C1-6alkyl; n1, n2 and n3 are independently 0 or 1; R3is C3-12cycloalkyl, C3-12cycloalkyl substituted with one or more R3-1, “4- to 12-membered heterocycloalkyl containing 1–3 heteroatoms independently selected from O, S and N”, “4- to 12- membered heterocycloalkyl containing 1–3 heteroatoms independently selected from O, S and N” substituted with one or more R3-2, C1-6alkyl, C1-6alkyl substituted with one or more R3-3, C2-6alkenyl substituted with one or more R3-4, -ORd, -SRd1, -NRe1Re2or -C(=O)NRe3Re4; provided that when multiple substituents are present, the substituents are the same or different; R3-1, R3-2, R3-3and R3-4are independently C1-6alkyl, C1-6alkyl substituted with one or more R3-1-1, C6-20aryl substituted with one or more R3-1-5, hydroxyl, azide, Ar, C1-6alkyl-O-, -CH2-O-Ar, halogen, O=, -NRe5Re6, -C(=O)NRe7Re8orAr is "5-12-membered heteroaryl containing 1-3heteroatoms independently selected from O, N and S" substituted with one or more R3-1-4; or, R3-1and R3-2are independently -L2-M; L2is -L21-L22-L23-L24-L25-L26; L21, L23and L25are independently a bond, O, S, NH, C(O)NH or C1-6alkylene; L22and L24are independently a bond, C3-10cycloalkyl, “4- to 7-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O, S and N”, C6-20aryl, or , “5- to 7-membered heteroaryl containing 1 or 2 heteroatoms independently selected from O, S, and N”; L26is a bond, O, S, NH or C(O)NH;R4g, R4h, Re17and Re18are independently hydrogen, halogen, C1-6alkyl, C1-6alkyl substituted with one or more halogen, cyano, -C(=O)Re171, -C(=O)ORe172or -C(=O)NRe173Re174; or, R4gand R4h, Re17and Re18, together with the atom to which they are attached form 3- to 8-membered carbocyclic ring, or “4- to 8-membered heterocyclic ring containing 1 to 3 heteroatoms independently selected from O, S, and N”; Rd, Rd1, Re1, Re2, Re3and Re4are independently hydrogen, C1-6alkyl, C3-10cycloalkyl, “4- to 10- membered heterocycloalkyl containing 1–3 heteroatoms independently selected from O, S and N”, or, C1-6alkyl substituted with one or more R3-1-2; R3-1-1, R3-1-2, R3-1-5and R3-1-4are independently deuterium, cyano, halogen, hydroxyl, C1-6alkyl, C2-6alkenyl, C1-6alkyl-O-, C1-6alkyl-O- substituted with one or more halogen, C1-6alkyl substituted with one or more halogen, -C(=O)Re9, -NRe10Re11, -C(=O)ORe12, -C(=O)NRe13Re14, - OC(=O)NRe15Re16, “4- to 10-membered heterocycloalkyl containing 1–3 heteroatoms independently selected from O, S and N”, or, “4- to 10-membered heterocycloalkyl containing 1–3 heteroatoms independently selected from O, S and N” substituted with one or more R3-1-1-1; or, two optional R3-1-5are connected, together with the atoms to which they are attached form “4- to 10- membered heterocycloalkyl containing 1–3 heteroatoms independently selected from O, S and N” substituted with one or more R3-1-1-2; R3-1-1-1and R3-1-1-2are independentlyhalogen,C1-6 alkyl or C6-20 aryl substituted with oneor more R3-1-1-1-1; R3-1-1-1-1is halogen or C1-6alkyl substituted with one or more halogen; Re5, Re6, Re7, Re8, Re9, Re10, Re11, Re12, Re13, Re14, Re15, Re16, Re171, Re172, Re173and Re174are independently hydrogen or C1-6alkyl; or, R12and R13, R15and R16, Rc3and Rc4, R22and R23, R25and R26, R4b1and R4b2, R4d1and R4d2, R4f1and R4f2, R4iand R4j, Re1and Re2, Re3and Re4, Re5and Re6, Re7and Re8, Re10and Re11, Re13and Re14, Re15and Re16, Re173and Re174together with the atom N to which they are attached form “4- to 12-membered heterocycloalkyl containing 1–3 heteroatoms, of which one is N, the other independently selected from O, S and N”, or , “4- to 12-membered heterocycloalkyl containing 1–3 heteroatoms, of which one is N, the other independently selected from O, S and N” substituted with one or more R3-1-3; R3-1-3is independently deuterium, cyano, halogen, hydroxyl, C1-6alkyl-O-, C1-6alkyl, C1-6alkyl substituted with one or more R33, “4- to 7-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O, S and N” or -C(=O)OR30; Rc51, Rc52, R11, R21, R14, R15, R16, R24, R25, R26, R27, R28and R30are independently hydrogen or C1-6alkyl; R29is hydrogen, C1-6alkyl or -NRmRn; R31is hydrogen, C1-6alkyl, -OC1-6alkyl, -NRmRn, -OC(=O)R32or -C(=O)OC1-6alkyl; R32and R33are independently -OC1-6alkyl or C1-6alkyl substituted with one or more -NRmRn; R22, R23, Rmand Rnare independently hydrogen, C1-6alkyl or Boc.

2. The nitrogen-containing heterocyclic compound of formula I, the pharmaceutically acceptable salt thereof, a prodrug thereof, a stereoisomer thereof a tautomer thereof or an isotopically labeled compound thereof according to claim 1, wherein, represents a single or double bond;is phenyl, “5- to 7-membered heterocycloalkenyl containing 1–3 heteroatoms independently selected from O, S and N” or “5- to 7-membered heteroaryl containing 1–3 heteroatoms independently selected from O, S and N”; wherein D1is C, CH or N; D2is, wherein Z1and Z2are independently a bond, CH, CH2, O, S, N or NH; r is 0, 1 or 2; R5is independently halogen, C1-6alkyl, C1-6alkyl substituted with one or more halogen, hydroxyl, C1-6alkyl-O-, C2-6alkenyl or nitro; Y1is O, NH, CH2orY2is NR2or O; m1, m2 and n are independently 0, 1, 2, 3 or 4;X1and X2are N; R1is C6-20aryl, “5- to 12-membered heteroaryl containing 1–4 heteroatoms independently selected from O, S and N”, C6-20aryl substituted with one or more R1-1or “5- to 12-membered heteroaryl containing 1–4 heteroatoms independently selected from O, S and N” substituted with one or more R1-2; provided that when multiple substituents are present, the substituents are the same or different; R1-1and R1-2are independently halogen, -ORc, cyano, -NR12R13, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -B(ORx) (ORy) or C1-6alkyl substituted by one or more R1-1-1; provided that when multiple substituents are present, the substituents are the same or different; R2, Rc, R12and R13are independently hydrogen, C1-6alkyl, -C(=O)Rc1, -C(=O)ORc2, - C(=O)NRc3Rc4, -SO2Rc5, , or C1-6alkyl substituted with one or more Rc10;Rc1, Rc2, Rc3, Rc4, Rc5, Rc6, Rc7, Rc8and Rc9are independently hydrogen, C1-20alkyl, C3-10cycloalkyl, C1-20alkyl substituted with one or more R4-1-1, C6-20aryl substituted with one or more R4-1-4, “5- to 7-membered heteroaryl containing 1 or 2 heteroatoms independently selected from O, S and N” , “5- to 7-membered heteroaryl containing 1 or 2 heteroatoms independently selected from O, S and N” substituted with one or more R4-1-5, -NRc51Rc52, -(C1-6alkylene-O)p-C1-6alkyl, ; p is 1, 2, 3 or 4; provided that when multiple substituentsare present, the substituents are the same or different; R1-1-1, R4-1-1, R4-1-4and R4-1-5are independently halogen, hydroxyl, C1-6alkyl-O-, C1-6alkyl substituted with one or more R31, “4- to 7-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O, S, and N”, C6-20aryl, -C(=O)R21, -NR22R23, -C(=O)OR24, - OC(=O)R32, -COOH, -C(=O)OR27or -OC(=O)OR28; Rc10is -OC1-6alkyl, hydroxyl, substituted with C1-6alkyl, C6-20aryl substituted with one ormore -B(ORx)(ORy), “5- to 7-membered heteroaryl containing 1 or 2 heteroatoms independentlyselected from O, S, and N” substituted with one or more Rc10-1,or -OC(=O)R29; Rc10-1is independently C1-6alkyl or nitro;or, optional R2and R5together with the atoms to which they are attached, independently form “5- to 12-membered heterocyclic alkenyl containing 2 to 4 heteroatoms, two of which are N, and the other heteroatoms independently selected from O, S, and N”; Rxand Ryare independently hydrogen or C1-6alkyl, or Rxand Ryeach with the attached oxygen atom form five-membered ring substituted with one or more C1-6alkyl; R4is independently deuterium, halogen, hydroxyl, C1-6alkyl, O= or -C(=O)R4a; or, when n is 2, 3 or 4, two optional R4are connected, together with the atoms to which they are attached form “4- to 8-membered heterocyclic ring containing 1 to 3 heteroatoms independently selected from O, S, and N” substituted with one or more R4-5; R4-5is O=; R4ais C1-6alkyl or C2-6alkenyl; L1is a bond or -O(RL-1)n1-; RL-1is C1-6alkylene or C1-6alkylene substituted with one or more deuterium ; n1 is 1; R3is C3-12cycloalkyl substituted with one or more R3-1, “4- to 12-membered heterocycloalkyl containing 1–3 heteroatoms independently selected from O, S and N”, “4- to 12-membered heterocycloalkyl containing 1–3 heteroatoms independently selected from O, S and N” substituted with one or more R3-2or C2-6alkenyl substituted with one or more R3-4; provided that when multiple substituents are present, the substituents are the same or different; R3-1, R3-2and R3-4are independently C1-6alkyl, C1-6alkyl substituted with one or more R3-1-1, C6-20aryl substituted with one or more R3-1-5, Ar, C1-6alkyl-O-, -CH2-O-Ar, halogen oAr is "5-12-membered heteroaryl containing 1-3 heteroatoms independently selected from O, N and S" substituted with one or more R3-1-4; R3-1-1, R3-1-5and R3-1-4are independently halogen, C1-6alkyl, C2-6alkenyl, C1-6alkyl-O- substituted with one or more halogen, C1-6alkyl substituted with one or more halogen, -C(=O)Re9, -NRe10Re11, -OC(=O)NRe15Re16, “4- to 10-membered heterocycloalkyl containing 1–3 heteroatoms independently selected from O, S and N”, or , “4- to 10-membered heterocycloalkyl containing1–3 heteroatoms independently selected from O, S and N” substituted with one or more R3-1-1-1; or, two optional R3-1-5are connected, together with the atoms to which they are attached form “4- to 10-membered heterocycloalkyl containing 1–3 heteroatoms independently selected from O, S and N” substituted with one or more R3-1-1-2; R3-1-1-1and R3-1-1-2are independentlyhalogen,C1-6 alkyl or C6-20 aryl substituted with oneor more R3-1-1-1-1; R3-1-1-1-1is independently halogen or C1-6alkyl substituted with one or more halogen; or, R3-1and R3-2are independently -L2-M; L2is -L21-L22-L23-L24-L25-L26; L21, L23and L25are independently a bond, O, S, NH, C(O)NH or C1-6alkylene; L22and L24are independently a bond, C3-10cycloalkyl, “4- to 7-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O, S and N”, C6-20aryl, or , “5- to 7-membered heteroaryl containing 1 or 2 heteroatoms independently selected from O, S, and N”; L26is a bond, O, S, NH or C(O)NH;Re17and Re18are independentlyhydrogen or halogen; Re9, Re10, Re11, Re15and Re16are independently hydrogen or C1-6alkyl; or, Rc3and Rc4together with the atom N to which they are attached form “4- to 12-membered heterocycloalkyl containing 1–3 heteroatoms, of which one is N, the other independently selected from O, S and N”, or , “4- to 10-membered heterocycloalkyl containing 1–3 heteroatoms, of which one is N, the other independently selected from O, S and N” substituted with one or more R3-1-3; R3-1-3is independently C1-6alkyl substituted with one or more R33, “4- to 7-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O, S and N” or -C(=O)OR30; Rc51, Rc52, R24, R27, R28and R30are independently hydrogen or C1-6alkyl; R29is hydrogen, C1-6alkyl or -NRmRn; R31is hydrogen, C1-6alkyl, -OC1-6alkyl, -NRmRn, -OC(=O)R32or -C(=O)OC1-6alkyl;R32and R33are independently-OC1-6alkyl or C1-6alkyl substituted with one or more -NRmRn; R21, R22, R23, Rmand Rnare independently hydrogen, C1-6alkyl or Boc.

3. The nitrogen-containing heterocyclic compound of formula I, the pharmaceutically acceptable salt thereof, a prodrug thereof, a stereoisomer thereof, a tautomer thereof or an isotopically labeled compound thereof according to claim 1 or 2, wherein, “ “ represents a single or double bond;is phenyl, “5- to 7-membered heterocycloalkenyl containing 1–3 heteroatoms independently selected from O, S and N” or “5- to 7-membered heteroaryl containing 1–3 heteroatoms independently selected from O, S and N”; wherein D1is C or N; D2is, wherein Z1and Z2are independently a bond, CH, CH2N or NH; r is 0, 1 or 2; R5is independently halogen, C1-6alkyl, C1-6alkyl substituted with one or more halogen, hydroxyl or C2-6alkenyl; Y1is O, NH, CH2orY2is NR2or O; R2is hydrogen, C1-6alkyl, -C(=O)Rc1or -C(=O)ORc2; Rc1is C1-20alkyl substituted with one or more R4-1-1; Rc2is C1-6alkyl; R4-1-1is independently halogen; m1and m2 are independently 0 or 1; n is 0, 1 or 2; R4is halogen, hydroxyl or C1-6alkyl; X1and X2are N; R1is C6-20aryl, “5- to 12-membered heteroaryl containing 1–4 heteroatoms independently selected from O, S and N”, C6-20aryl substituted with one or more R1-1or “5- to 12-membered heteroaryl containing 1–4 heteroatoms independently selected from O, S and N” substituted with one or more R1-2; provided that when multiple substituents are present, the substituents are the same or different;R1-1and R1-2are independently halogen, -ORc, cyano, -NR12R13, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -B(ORx) (ORy) or C1-6alkyl substituted by one or more R1-1-1; provided that when multiple substituents are present, the substituents are the same or different; Rcis hydrogen, -C(=O)Rc1, -C(=O)NRc3Rc4or C1-6alkyl substituted with one or more Rc10; Rc10is independently -OC(=O)R29; R29is -NRmRn; Rmand Rnare C1-6alkyl; Rc1, Rc3and Rc4are independently hydrogen, C1-20alkyl, C3-10cycloalkyl, -(C1-6alkylene-O)p-C1-6alkyl, C1-20alkyl substituted with one or more R4-1-1or C6-20aryl substituted with one or more R4-1-4; p is 1, 2 or 3; R4-1-1is independently C1-6alkyl-O-, -C(=O)R21, -NR22R23, -COOH or “4- to 7-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O, S, and N”; R21is C1-6alkyl; R22and R23are independently hydrogen, C1-6alkyl or Boc; R4-1-4is halogen; or, Rc3and Rc4together with the atom N to which they are attached form “4- to 12-membered heterocycloalkyl containing 1–3 heteroatoms, of which one is N, the other independently selected from O, S and N”, or , “4- to 12-membered heterocycloalkyl containing 1–3 heteroatoms, of which one is N, the other independently selected from O, S and N” substituted with one or more R3-1-3; R3-1-3is independently C1-6alkyl substituted with one or more R33or “4- to 7-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O, S and N”; R33is independently -OC1-6alkyl; R12and R13are independently hydrogen; Rxand Ryare independently hydrogen; R1-1-1is halogen; L1is a bond or -O(RL-1)n1-; RL-1is C1-6alkylene or C1-6alkylene substituted with one or more deuterium; n1 is 1; R3is C3-12cycloalkyl substituted with one or more R3-1, “4- to 12-membered heterocycloalkyl containing 1–3 heteroatoms independently selected from O, S and N”, “4- to 12-membered heterocycloalkyl containing 1–3 heteroatoms independently selected from O, S and N” substituted with one or more R3-2or C2-6alkenyl substituted with one or more R3-4; provided that when multiple substituents are present, the substituents are the same or different;R3-1is independently C1-6alkyl substituted with one or more R3-1-1; R3-1-1is independently - NRe10Re11, “4- to 10-membered heterocycloalkyl containing 1–3 heteroatoms independently selected from O, S and N”, or , “4- to 10-membered heterocycloalkyl containing 1–3 heteroatoms independently selected from O, S and N” substituted with one or more R3-1-1-1; Re10and Re11are independently C1-6alkyl; R3-1-1-1is independently,C1-6 alkyl or C6-20 aryl substituted withone or more R3-1-1-1-1; R3-1-1-1-1is independently halogen; R3-2is independently halogen, Cal3-1-11-6 kyl,C1-6 alkyl substituted with one or more R ,Ar, -CH2-O-Ar or C6-20aryl substituted with one or more R3-1-5; Ar is “5-12-membered heteroaryl containing 1-3 heteroatoms independently selected from O, N and S” substituted with one or more R3-1-4; R3-1-1is halogen, C2-6alkenyl or -OC(=O)NRe15Re16; Re15and Re16are independently C1-6alkyl; R3-1-5and R3-1-4are independently C1-6alkyl, halogen, C1-6alkyl-O- substituted with one or more halogen or C1-6alkyl substituted with one or more halogen; or, two optional R3-1-5are connected, together with the atoms to which they are attached form “4- to 10-membered heterocycloalkyl containing 1–3 heteroatoms independently selected from O, S and N” substituted with one or more R3-1-1-2; R3-1-1-2is independently halogen; or, R3-1is -L2-M; L2is -L21-L22-L23-L24-L25-L26; L21, L23and L25are independently a bond, O, S, NH, C(O)NH or C1-6alkylene; L22and L24are independently a bond, C3-10cycloalkyl, “4- to 7-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O, S and N”, C6-20aryl, or , “5- to 7-membered heteroaryl containing 1 or 2 heteroatoms independently selected from O, S, and N”; L26is a bond, O, S, NH or C(O)NH;R3-4is independently halogen or C1-6alkyl substituted with one or more R3-1-1; R3-1-1is independently -NRe10Re11or “4- to 10-membered heterocycloalkyl containing 1–3 heteroatoms independently selected from O, S and N”; Re10and Re11are independently C1-6alkyl;Re17and Re18are independently hydrogen or halogen.

4. The nitrogen-containing heterocyclic compound of formula I, the pharmaceutically acceptable salt thereof, a prodrug thereof, a stereoisomer thereof, a tautomer thereof or an isotopically labeled compound thereof according to claim 1, wherein, D1is C or N; and / or, in D2, one of Z1and Z2is CH, CH2or N; the other one is a bond; and / or, r is 0, 1 or 2; and / or, R5is independently halogen, C1-6alkyl, C1-6alkyl substituted with one or more halogen, hydroxyl, C1-6alkyl-O-, C2-6alkenyl or nitro; and / or, X1and X2are N; and / or, R1-1is independently halogen, -ORc, C1-6alkyl, -NR12R13, C2-6alkynyl or C1-6alkyl substituted by one or more R1-1-1; provided that when multiple substituents are present, the substituents are the same or different; R1-1-1is independently halogen; and / or, R1-2is independently halogen, cyano, C2-6alkenyl or -NR12R13; and / or, R12and R13are independently hydrogen, -SO2Rc5or -C(=O)ORc2; Rc2is C1-6alkyl; and / or, Rcis hydrogen, -C(=O)Rc1, -C(=O)ORc2, -C(=O)NRc3Rc4, -SO2Rc5,or C1-6alkyl substituted with one or more Rc10; Rc10is independently -OC1-6alkyl,substituted with C1-6alkyl, C6-20aryl substituted with one or more -B(ORx)(ORy), “5- to 7- membered heteroaryl containing 1 or 2 heteroatoms independently selected from O, S, and N” substituted with one or more Rc10-1,29 c10-1or -OC(=O)R ; R is independentlyC1-6 alkylor nitro; Rc1, Rc2, Rc3, Rc4, Rc5, Rc6, Rc7, Rc8and Rc9are independently hydrogen, C1-20alkyl, C3-10cycloalkyl, C1-20alkyl substituted with one or more R4-1-1, C6-20aryl substituted with one or more R4-1-4, “5- to 7-membered heteroaryl containing 1 or 2 heteroatoms independently selected from O, S and N” , “5- to 7-membered heteroaryl containing 1 or 2 heteroatoms independently selected fromO, S and N” substituted with one or more R4-1-5, -NRc51Rc52, -(C1-6alkylene-O)p-C1-6alkyl,p is 1, 2, 3 or 4; provided that when multiple substituents are present, the substituents are the same or different; R1-1-1, R4-1-1, R4-1-4and R4-1-5are independently halogen, hydroxyl, C1-6alkyl-O-, C1-6alkyl, C1-6alkyl substituted with one or more R31, “4- to 7- membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O, S, and N”, C6-20aryl, “5- to 7-membered heteroaryl containing 1 or 2 heteroatoms independently selected from O, S and N”, -NR22R23, -C(=O)OR24, -OC(=O)R32, -COOH, -C(=O)OR27or -OC(=O)OR28; Rxand Ryare independently hydrogen, or Rxand Ryeach with the attached oxygen atom form five- membered ring substituted with one or more C1-6alkyl; or, Rc3and Rc4together with the atom N to which they are attached form “4- to 12-membered heterocycloalkyl containing 1–3 heteroatoms, of which one is N, the other independently selected from O, S and N”, or, “4- to 12-membered heterocycloalkyl containing 1–3 heteroatoms, of which one is N, the other independently selected from O, S and N” substituted with one or more R3-1-3; R3-1-3is independently C1-6alkyl substituted with one or more R33, “4- to 7-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O, S and N” or -C(=O)OR30; R30is hydrogen or C1-6alkyl; R33is independently-OC1-6alkyl or C1-6alkyl substituted with one or more - NRmRn; Rmand Rnare independently hydrogen, C1-6alkyl or Boc; and / or, when R1is C6-20aryl substituted with one or more R1-1, the more is two or three; and / or, Y1is O, NH, CH2orand / or, m1, m2 and n are independently 0, 1 or 2; and / or, Y2is O or NR2; and / or, R2is hydrogen, C1-6alkyl, -C(=O)Rc1or -C(=O)ORc2; Rc1is C1-20alkyl or C1-20alkyl substituted with one or more R4-1-1; Rc2is C1-6alkyl or C1-6alkyl substituted with one or more R4-1-1; R4-1-1is independently halogen, C6-20aryl or -OC(=O)R24; or, optional R2and R5together with the atoms to which they are attached, independently form “5- to 12-membered heterocyclic alkenyl containing 2 to 4 heteroatoms, two of which are N, and the other heteroatoms independently selected from O, S, and N”;and / or, R24is C1-6alkyl; and / or, R4is independently halogen, hydroxyl, deuterium, -C(=O)R4a, O= or C1-6alkyl; R4ais C1-6alkyl or C2-6alkenyl; and / or, L1is a bond or -O(RL-1)n1-; RL-1is C1-6alkylene or C1-6alkylene substituted with one or more deuterium ; n1 is 1; and / or, R3is C3-12cycloalkyl substituted with one or more R3-1, “4- to 12-membered heterocycloalkyl containing 1–3 heteroatoms independently selected from O, S and N”, “4- to 12- membered heterocycloalkyl containing 1–3 heteroatoms independently selected from O, S and N” substituted with one or more R3-2or C2-6alkenyl substituted with one or more R3-4; provided that when multiple substituents are present, the substituents are the same or different; and / or, R3-1is independently C1-6alkyl substituted with one or more R3-1-1; R3-1-1is independently - NRe10Re11, “4- to 10-membered heterocycloalkyl containing 1–3 heteroatoms independently selected from O, S and N”, or , “4- to 10-membered heterocycloalkyl containing 1–3 heteroatoms independently selected from O, S and N” substituted with one or more R3-1-1-1; Re10and Re11are independently C1-6alkyl; R3-1-1-1is independently C1-6 alkyl or C6-20 aryl substituted withone or more R3-1-1-1-1; R3-1-1-1-1is independently halogen or C1-6alkyl substituted with one or more halogen; Re17and Re18are independently hydrogen or halogen; or, R3-1is -L2-M; L2is -L21-L22-L23- L24-L25-L26; L21, L23and L25are independently a bond, O, S, NH, C(O)NH or C1-6alkylene; L22and L24are independently a bond, C3-10cycloalkyl, “4- to 7-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O, S and N”, C6-20aryl, or , “5- to 7-membered heteroaryl containing 1 or 2 heteroatoms independently selected from O, S, and N”; L26is a bond, O, S, NH or C(O)NH;and / or, R3-2is independently halogen, C1-6alkyl,,C1-6 alkyl substituted with one or moreR3-1-1, Ar, -CH2-O-Ar or C6-20aryl substituted with one or more R3-1-5; Ar is “5-12-membered heteroaryl containing 1-3 heteroatoms independently selected from O, N and S” substituted with one or more R3-1-4; R3-1-1is halogen, C2-6alkenyl or -OC(=O)NRe15Re16; Re15and Re16are independently C1-6alkyl; Re17and Re18are independently hydrogen or halogen; R3-1-5and R3-1-4are independently C1-6alkyl, halogen, C1-6alkyl-O- substituted with one or more halogen or C1-6alkyl substituted with one or more halogen; or, two optional R3-1-5are connected, together with the atoms to which they are attached form “4- to 10-membered heterocycloalkyl containing 1–3 heteroatoms independently selected from O, S and N” substituted with one or more R3-1-1-2; R3-1-1-2is independently halogen; and / or, R3-4is independently halogen or C1-6alkyl substituted with one or more R3-1-1; R3-1-1is independently -NRe10Re11or “4- to 10-membered heterocycloalkyl containing 1–3 heteroatoms independently selected from O, S and N”; Re10and Re11are independently C1-6alkyl.

5. The nitrogen-containing heterocyclic compound of formula I, the pharmaceutically acceptable salt thereof, a prodrug thereof, a stereoisomer thereof, a tautomer thereof or an isotopically labeled compound thereof according to claim 1, wherein, when r is 1,and / or, m1and m2 are independently is 0 or 1; and / or, Re17and Re18are independently is hydrogen or halogen; and / or, when the definition of R5, Rb, R1-1, R1-2, R1-1-1, R1-1-2, R1-1-3, R1-1-4, R1-1-5, R1-1-6, R4-1-1, R4-1-2, R4-1-3, R4-1-4, R4-1-5, R4, R4-1, R4-2, R4-3, R4-4, R4-5, Ra, R3-1, R3-2, R3-3, R3-4, R3-1-1, R3-1-2, R3-1-3, R3-1-5, R3-1-4, R4g, R4h, Re17, Re18, R3-1-1-1and R3-1-1-1-1mentions halogen, the halogen is fluorine, chlorine, bromine or iodine; and / or, when the definition of R1, R1-1, R1-2, Rc1, Rc2, Rc3, Rc4, Rc5, Rc6, Rc7, Rc8, Rc9, R1-1-1, R1-1-2, R1-1-3, R1-1-4, R1-1-5, R1-1-6, R4-1-1, R4-1-2, R4-1-3, R4-1-4, R4-1-5, Rc10, R3-1, R3-2, R3-3, R3-4and R3-1-1-1mentions C6-20aryl, the C6-20aryl is phenyl or naphthyl;and / or, when the definition of R5, R1-1, R1-2, R2, Rc, R12, R13, Rc10, Rc10-1, R1-1-1, R1-1-2, R1-1-3, R1-1-4, R1-1-5, R1-1-6, R4-1-1, R4-1-2, R4-1-3, R4-1-4, R4-1-5, Rc51, Rc52, R11, R21, R22, R23, R14, R24, R15, R25, R16, R26, R27, R28, R29, R30, R31, R32, R33, Rx, Ry, R4, R4-1, R4-2, R4-3, R4-4, R4-5, Ra, R4a, R4b1, R4b2, R4c, R4d1, R4d2, R4e, R4f1, R4f2, R4i, R4j, RL-3, R3, R3-1, R3-2, R3-3, R3-4, R4g, R4h, Re17, Re18, Rd, Rd1, Re1, Re2, Re3, Re4, R3-1-1, R3-1-2, R3-1-5, R3-1-4, R3-1-1-1, R3-1-1-1-1, Re5, Re6, Re7, Re8, Re9, Re10, Re11, Re12, Re13, Re14, Re15, Re16, Re171, Re172, Re173, Re174and R3-1-3的 mentions C1-6alkyl, the C1-6alkyl is C1-4alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl; and / or, when the definition of Rc1, Rc2, Rc3, Rc4, Rc5, Rc6, Rc7, Rc8and Rc9independently is C1-20alkyl, the C1-20alkyl is C1-12alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec- butyl, isobutyl or tert-butyl; and / or, when the definition of R1-1, R1-2and R4mentions C2-6alkynyl, the C2-6alkynyl is ethynyl, propynyl or propargyl; and / or, when the definition of R5, R1-1, R1-2, R4, R4-1, R4-2, R4-3, R4-4, R4-5, Ra, R4a, R4b1, R4b2, R4c, R4d1, R4d2, R4e, R4f1, R4f2, R4i, R4j, R3, R3-1-1, R3-1-2, R3-1-5and R3-1-4mentions C2-6alkenyl, the C2-6alkenyl is vinyl, propenyl or allyl.

6. The nitrogen-containing heterocyclic compound of formula I, the pharmaceutically acceptable salt thereof, a prodrug thereof, a stereoisomer thereof, a tautomer thereof or an isotopically labeled compound thereof according to claim 1, wherein, R4is independently methyl, F, D, 0xo, or hydroxyl;and / or,and / or, R5is independently -F, -OH, -Cl, -CF3, , , -NO2, -OEt or -OMe, or, R2and R5formFBand / or, L1is a bond, -OCH2- or -OCD2-;7. The nitrogen-containing heterocyclic compound of formula I, the pharmaceutically acceptable salt thereof, a prodrug thereof, a stereoisomer thereof, a tautomer thereof or an isotopically labeled compound thereof according to claim 1, wherein,8. The nitrogen-containing heterocyclic compound of formula I, the pharmaceutically acceptable salt thereof, a prodrug thereof, a stereoisomer thereof, a tautomer thereof or an isotopically labeled compound thereof according to claim 1, wherein,9. A compound has any one of the following structures:F。 10. A pharmaceutical composition comprising a substance A and a pharmaceutically acceptable excipient, wherein the substance A is a therapeutically effective amount of the nitrogen-containingheterocyclic compound of formula I, the pharmaceutically acceptable salt thereof, the prodrug therof, the stereoisomer thereof, the tautomer thereof or the isotopically labeled compound thereof according to any one of claims 1-8.

11. A method for inhibiting RAS in a subject in need thereof, comprising: administering a therapeutically effective amount of a substance A to the subject, wherein the substance A is the compound containing structure of a nitrogen-containing heterocyclic compound of formula I, the pharmaceutically acceptable salt thereof, the prodrug therof, the stereoisomer thereof, the tautomer thereof or the isotopically labeled compound thereof according to claim 1. The RAS is wild type RAS or mutated forms of RAS; the wild type RAS is wild-amplified KRAS; the mutated forms of RAS are a KRAS, HRAS or NRAS mutation.

12. A method for treating or preventing a RAS-related disease in a subject in need thereof, comprising: administering a therapeutically effective amount of a substance A to the subject, wherein the substance A is the compound containing structure of the nitrogen-containing heterocyclic compound of formula I, the pharmaceutically acceptable salt thereof, the prodrug therof, the stereoisomer thereof, the tautomer thereof or the isotopically labeled compound thereof according to claim 1; the cancer is selected from the group consisting of colon cancer, appendiceal cancer, pancreatic cancer, MYH-related polyposis, hematologic cancer, breast cancer, endometrial cancer, gallbladder cancer, bile duct cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, cervical cancer, testicular cancer, kidney cancer, head or neck cancer, bone cancer, skin cancer, rectal cancer, liver cancer, esophageal cancer, stomach cancer, thyroid cancer, bladder cancer, lymphoma, leukemia and melanoma.

13. A method for treating or preventing cancer in a subject in need thereof, comprising: administering a therapeutically effective amount of a substance A to the subject, wherein the substance A is the compound containing structure of the nitrogen-containing heterocyclic compound of formula I, the pharmaceutically acceptable salt thereof, the prodrug therof, the stereoisomer thereof, the tautomer thereof or the isotopically labeled compound thereof according to claim 1; the cancer is selected from the group consisting of colon cancer, appendiceal cancer, pancreatic cancer, MYH-related polyposis, hematologic cancer, breast cancer, endometrial cancer, gallbladder cancer, bile duct cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, cervical cancer, testicularcancer, kidney cancer, head or neck cancer, bone cancer, skin cancer, rectal cancer, liver cancer, esophageal cancer, stomach cancer, thyroid cancer, bladder cancer, lymphoma, leukemia and melanoma.

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